aa5669fe641fb39d7711eb81ec05092d14f267fb lrnassar Tue Jun 30 15:20:56 2026 -0700 Adding Cardiomyopathy VCEP track hub build scripts and makedoc. refs #37446 Adds the 12 per-track build scripts under src/hg/makeDb/scripts/cardiomyopathyVCEP/ (gnomAD v4.1 allele frequencies, REVEL, CardioBoost, the hgVai consequence/HGVSp annotation layer, ClinGen EvRepo, ClinVar submitter 506161, Walsh 2019 curations, PM1 clinical-domain hotspots, MYBPC3 PVS1 caveats, Walsh 2017 PS4 odds-ratio track, Atlas PS4 per-variant OR, and the NON-FINAL provisional classifier) plus the build documentation at src/hg/makeDb/doc/Cardiomyopathy.txt. All ACMG thresholds are taken directly from the ClinGen Cardiomyopathy CSpecs (8 genes, affiliation 50002); no thresholds are invented in the build. diff --git src/hg/makeDb/doc/Cardiomyopathy.txt src/hg/makeDb/doc/Cardiomyopathy.txt new file mode 100644 index 00000000000..3d8315e1ce7 --- /dev/null +++ src/hg/makeDb/doc/Cardiomyopathy.txt @@ -0,0 +1,502 @@ +############################################################################## +# Cardiomyopathy VCEP Track Hub — build documentation +# +# Redmine: #37446 +# VCEP: https://clinicalgenome.org/affiliation/50002/ +# CSpec: https://cspec.genome.network/cspec/ui/svi/affiliation/50002 +# +# 8 gene/disease specifications, all dated 2024-04-22: +# GN002 MYH7 v2.0.0 HCM + DCM (AD) +# GN095 MYBPC3 v1.0.0 HCM (AD) — only PVS1-applicable gene +# GN098 TNNI3 v1.0.0 HCM (AD) +# GN099 TNNT2 v1.0.0 HCM + DCM (AD) +# GN100 TPM1 v1.0.0 HCM (AD) +# GN101 ACTC1 v1.0.0 HCM (AD) +# GN102 MYL2 v1.0.0 HCM (AD) +# GN103 MYL3 v1.0.0 HCM (AD) +# +# ARVC genes are out of scope (separate ClinGen panel, affiliation 40003). +# +# Expert contacts: +# Lucas Bronicki, PhD, FACMG — Cardiomyopathy VCEP Chair +# Haley Garrett, MPH — Coordinator (Haley_Garrett@med.unc.edu) +# ClinVar submitter ID: 506161 ("ClinGen Cardiomyopathy Variant +# Curation Expert Panel") +# +# Calibration sources: +# Walsh 2017 (PMID 27532257; Genet Med; DOI 10.1038/gim.2016.90) +# — PS4 case-control reference (Tables S5A/S5B; +# 60,706 ExAC samples; 7,855 cases) +# Walsh 2019 (PMID 30696458; Genome Medicine; DOI 10.1186/s13073-019-0616-z) +# — PM1 hotspot codon ranges (Table S4), +# per-gene NonTrunc ExAC denominators +# (Table S1), and 155 pre-EvRepo per-variant +# curations (Table S6) +# +# MANE Select transcripts (verified against /gbdb/hg38/mane/mane.bb): +# MYH7 NM_000257.4 NP_000248.2 chr14 (-) +# MYBPC3 NM_000256.3 NP_000247.2 chr11 (-) +# TNNT2 NM_001276345.2 NP_001263274.1 chr1 (-) +# TNNI3 NM_000363.5 NP_000354.4 chr19 (-) +# TPM1 NM_001018005.2 NP_001018005.1 chr15 (+) ← only plus-strand gene +# ACTC1 NM_005159.5 NP_005150.1 chr15 (-) +# MYL2 NM_000432.4 NP_000423.2 chr12 (-) +# MYL3 NM_000258.3 NP_000249.1 chr3 (-) +# +# NOTE on transcripts: the hgVai annotation layer (B.6) and most tracks use the +# MANE Select transcript above. Two deliberate exceptions: +# - TNNT2 PM1 codon range (B.1) and the Walsh-2019 TNNT2 curations (B.7c) use +# the classic NM_001001430.2 where the source data is keyed to it; TNNT2 +# hg19 coordinates for those are derived by liftOver from hg38 (no hg19 +# transcript alignment). The MANE PM1 range 89-189 is used for the PM1 track. +############################################################################## + + +############################################################################## +# Layout +############################################################################## +# +# Working directory: /hive/users/lrnassar/claude/RM37446/ +# hub.txt, genomes.txt +# hg38/trackDb.txt, hg19/trackDb.txt +# cardiomyopathy.html (shared description page) +# cmp_downloads/ (source data — checked at A.0 + cached) +# scripts_local_copy/ (insurance copy of all 12 build scripts; +# live copy is at ~/kent/...) +# cmpVCEPClinDomains/ (PM1 hotspot regions) +# cmpVCEPPVS1/ (MYBPC3-only PVS1 caveats) +# cmpVCEPAFfrequencies/ (gnomAD v4.1 BA1/BS1/PM2_supporting) +# cmpVCEPAnnotate/ (hgVai consequence + HGVSp annotation TSV) +# cmpVCEPRevel/ (REVEL PP3/BP4) +# cmpVCEPCardioBoost/ (CardioBoost missense predictor — off) +# cmpVCEPEvRepo/ (VCEP Curated Variants — EvRepo, with codes) +# cmpVCEPClinVar506161/ (VCEP ClinVar submissions, no codes) +# cmpVCEPWalsh2019/ (Walsh 2019 Pre-EvRepo Table S6 curations) +# cmpVCEPWalshOR/ (Walsh 2017 gene-level OR — PS4) +# cmpVCEPAtlasEF/ (Atlas of Cardiac Genetic Variation +# per-variant + UCSC-computed OR — PS4) +# cmpVCEPProvisionalClass/ (NON-FINAL combination-rule mockup) +# +# Build scripts: ~/kent/src/hg/makeDb/scripts/cardiomyopathyVCEP/ +# cmpVCEPClinDomains.py (B.1 — PM1 hotspot regions; also provides +# parse_mane_record, cds_exons, +# aa_to_genomic_segments helpers imported +# by B.2, B.6, B.9, B.11) +# cmpVCEPPVS1.py (B.2) +# cmpVCEPAFfrequencies.py (B.3; fetch_gene_variants() defines the +# shared variant universe reused by B.6/B.11) +# cmpVCEPAnnotate.py (B.6 — hgVai consequence/HGVSp annotation) +# cmpVCEPRevel.py (B.4) +# cmpVCEPCardioBoost.py (B.5) +# cmpVCEPEvRepo.py (B.7) +# cmpVCEPWalsh2019.py (B.7c) +# cmpVCEPClinVar506161.py (B.8) +# cmpVCEPWalshOR.py (B.9) +# cmpVCEPAtlasEF.py (B.10) +# cmpVCEPProvisionalClass.py (B.11) +# +# Otto cron staging dir: /hive/data/outside/otto/cardiomyopathyVCEP/ +# (NOT YET WRITTEN — Phase E TODO; mirror TP53) + + +############################################################################## +# Phase A: Source data +############################################################################## +# +# Working set lives in /hive/users/lrnassar/claude/RM37446/cmp_downloads/. +# Most files are downloaded once and re-used; EvRepo + ClinVar 506161 are the +# only sources intended for the weekly otto refresh (Phase E). Atlas is a +# one-time snapshot (ExAC-based; does not change weekly). +# +# A.0 MANE Select transcript verification + Walsh-paper roles per gene +# (FIRST ACTION — propagates through all downstream phases) +# +# Extract MANE bigGenePred for our 8 genes: +# bigBedToBed /gbdb/hg38/mane/mane.bb stdout \ +# | awk -F'\t' -v OFS='\t' ' +# BEGIN{print "geneSym\tchrom\tstart\tend\tstrand\trefSeqAcc\trefSeqProt\tensProtAcc"} +# $19 ~ /^(MYH7|MYBPC3|TNNT2|TNNI3|TPM1|ACTC1|MYL2|MYL3)$/ { +# print $19, $1, $2, $3, $6, $22, $24, $21 +# }' | sort > cmp_downloads/mane_8genes.tsv +# +# Walsh paper roles confirmed by parsing each CSpec HTML: +# PS4 source = Walsh 2017 universally (8/8 genes) +# PM1 calibration = Walsh 2019 (only MYH7, MYBPC3, TNNT2, TNNI3 — the +# 4 genes with a defined PM1 region) +# +# +# A.1 CSpec HTML pages (8 docs) +# +# mkdir -p cmp_downloads/cspec +# for gn in GN002 GN095 GN098 GN099 GN100 GN101 GN102 GN103; do +# curl -fsSL "https://cspec.genome.network/cspec/ui/svi/doc/${gn}" \ +# -o cmp_downloads/cspec/${gn}.html +# done +# +# Thresholds transcribed from the CSpec HTML (every value taken directly +# from the spec; none invented): +# BA1 universal: >= 0.001 (FAF95 popmax) +# BS1 universal (7 of 8): >= 0.0001 +# BS1 MYBPC3 outlier: >= 0.0002 (per GN095) +# PM2_supporting universal: <= 4e-05 +# PP3 REVEL universal: >= 0.70 +# BP4 REVEL universal: <= 0.40 +# PS4 OR (CI-lower) strength: Strong >=20, Moderate >=10, Supporting >=5 +# PM1 codon ranges: +# MYH7 167-931 (Walsh 2019 Table S4) +# MYBPC3 485-502 + 1248-1266 +# TNNT2 89-189 (MANE NM_001276345.2; classic NM_001001430.2 = 79-179) +# TNNI3 141-209 +# (TPM1, ACTC1, MYL2, MYL3 — no PM1 region defined) +# MYBPC3 PVS1 caveats: +# NMD-escape boundary: codon 1254+ +# Micro-exons: 10, 11, 14 +# In-frame exons: 2, 3, 4, 8, 9, 10, 11, 14, 20, 22, 24, 25, 26, 27 +# +# CSpec points where the spec is silent / leaves a curator choice (provisional +# decisions made for the build; posed to the VCEP for confirmation): +# - PS1/PM5 reference DB of "established pathogenic" (spec says "per +# Richards 2015", names none) — build uses VCEP EvRepo P/LP, leave-one-out. +# - PM4 for MYH7 (PVS1 N/A): spec redirects PM4 to non-NMD truncating at +# Moderate/Supporting, no boundary given — build uses last exon OR within +# 50 nt of the final exon-exon junction. +# - BP7 "not highly conserved": no metric/cutoff in spec — build uses +# phyloP470way <= 0 together with SpliceAI < 0.20. +# +# +# A.2 ClinGen EvRepo classifications (REST JSON) +# +# curl -fsSL 'https://erepo.genome.network/evrepo/api/classifications?expertpanel=Cardiomyopathy+VCEP&format=json' \ +# -o cmp_downloads/erepo/cardiomyopathyVCEP_classifications.json +# +# State at 2026-06-29 refresh: 25 variants (all MYH7). One change vs the +# April pull — CAR:CA016422 moved Likely Pathogenic -> Uncertain Significance. +# April JSON retained as *.april2026.json.bak. +# +# +# A.3 ClinVar submitter 506161 (filter from weekly VCV release) +# +# Precise column-10 match against the submission_summary (loose grep over- +# counts because the submitter name also appears in other submitters' text): +# zcat /hive/data/outside/otto/clinvar/downloads/$LATEST/submission_summary.txt.gz \ +# | awk -F'\t' '$10 == "ClinGen Cardiomyopathy Variant Curation Expert Panel"' \ +# > cmp_downloads/clinvar/cardiomyopathyVCEP_submissions.tsv +# +# State at ClinVar release 2026-05-30: 199 records, 100% "reviewed by +# expert panel". Classifications: 33 P + 32 LP + 75 VUS + 9 LB + 50 B = 199. +# +# +# A.4 gnomAD v4.1 exomes (already on hgwdev; no download) +# /hive/data/outside/gnomAD.4/v4.1/exomes/gnomad.exomes.v4.1.sites.chr{N}.vcf.bgz +# Field used: fafmax_faf95_max (max FAF95 across genetic ancestry groups), +# queried per-region via tabix. +# Public mirror: https://hgdownload.soe.ucsc.edu/gbdb/hg38/gnomAD/v4.1/exomes/exomes.bb +# +# A.5 REVEL (already on hgwdev; no download) +# /gbdb/hg38/revel/{a,c,g,t}.bw (per-alt-nucleotide bigwigs) +# Public mirror: https://hgdownload.soe.ucsc.edu/gbdb/hg38/revel/ +# +# A.6 SpliceAI (already on hgwdev; no download) +# /gbdb/hg38/bbi/spliceAi.bb (bed9+4; AIscore in col 9, name="ref>alt") +# Used by the B.11 SpliceAI safety net and BP7. +# +# A.7 CardioBoost precomputed predictions +# cmp_downloads/cardioboost/cm_prediction.RData (precomputed table, +# ~65k rows; ~31k in our 8 genes — NOT just model objects) +# Source: https://github.com/ImperialCardioGenetics/CardioBoost_manuscript +# Loaded via /usr/bin/Rscript (the team Rscript is broken on hgwdev — +# missing libgfortran.so.3). Coordinates are GRCh37 with numeric chrom +# names; B.5 adds the chr prefix and liftOvers to hg38. +# +# A.8 Walsh PS4 + PM1 calibration supplements +# mkdir -p cmp_downloads/walsh ; cd cmp_downloads/walsh +# # Walsh 2017 (PS4 case-control) — Springer direct (avoids PMC PoW challenge) +# curl -fsSL -o walsh2017_supplement.zip \ +# "https://static-content.springer.com/esm/art%3A10.1038%2Fgim.2016.90/MediaObjects/41436_2017_BFgim201690_MOESM9_ESM.zip" +# unzip -o walsh2017_supplement.zip # -> Supplementary_Tables_resubmit.xlsx +# # Walsh 2019 (PM1 calibration + NonTrunc denoms + Table S6 curations) +# curl -fsSL -o walsh2019_supplement.xlsx \ +# "https://static-content.springer.com/esm/art%3A10.1186%2Fs13073-019-0616-z/MediaObjects/13073_2019_616_MOESM1_ESM.xlsx" +# Walsh 2017 Tables S5A (HCM) / S5B (DCM): gene x disease x variant-class +# case-control OR + 95% CI (the PS4 source, B.9). +# Walsh 2019 Table S4: PM1 codon ranges. Table S1: per-gene NonTrunc ExAC +# denominators (B.10). Table S6: 155 per-variant ACMG curations (B.7c). +# +# A.9 Atlas of Cardiac Genetic Variation — one-time scrape with on-disk cache +# python3 cmp_downloads/atlas/scrape_atlas.py +# Two-pass (listing pages + per-variant pages for case_count >= 3), cached +# under cmp_downloads/atlas/raw/ + variants/, rate-limited 1.5 req/sec. +# The Atlas is a static companion to Walsh 2017 (ExAC controls, ~2016); it +# is NOT refreshed by otto. To refresh manually, delete the cache and re-run. + + +############################################################################## +# Phase B: Build tracks +############################################################################## +# +# All build scripts at ~/kent/src/hg/makeDb/scripts/cardiomyopathyVCEP/ +# Each accepts: --db hg38 --db hg19 --output-dir <path> (B.6 takes only +# --output-dir). Each emits .as / .bed / .bb for both assemblies and verifies +# cross-assembly parity at the end. +# +# Build order matters: B.3 defines the variant universe that B.6 annotates; +# B.11 (Provisional) consumes B.6 (annotation), B.3 (AF), B.4 (REVEL), and the +# B.7 EvRepo P/LP set (PS1/PM5 reference). Suggested order: +# +# for s in cmpVCEPClinDomains cmpVCEPPVS1 cmpVCEPAFfrequencies cmpVCEPAnnotate \ +# cmpVCEPRevel cmpVCEPCardioBoost cmpVCEPEvRepo cmpVCEPWalsh2019 \ +# cmpVCEPClinVar506161 cmpVCEPWalshOR cmpVCEPAtlasEF \ +# cmpVCEPProvisionalClass; do +# python3 ~/kent/src/hg/makeDb/scripts/cardiomyopathyVCEP/${s}.py \ +# --db hg38 --db hg19 \ +# --output-dir /hive/users/lrnassar/claude/RM37446 || break +# done +# # (cmpVCEPAnnotate.py takes only --output-dir.) +# +# +# B.1 cmpVCEPClinDomains.py — PM1 Hotspot Regions +# Output: 28 features (4 genes x CDS-exon-spanning AA range; MYH7, MYBPC3, +# TNNT2, TNNI3 only). Codon ranges per A.1. Color 230,3,131 (magenta-rose, +# the InSiGHT/TP53 clinical-domains convention). Built-in unit tests check +# codon-to-genomic conversion across all 8 genes. +# +# B.2 cmpVCEPPVS1.py — MYBPC3 PVS1 Evidence (MYBPC3 only) +# Output: 16 features (2 NMD-escape genomic segments + 14 in-frame exon +# caveats; 3 also tagged micro-exon in the mouseover). +# +# B.3 cmpVCEPAFfrequencies.py — gnomAD v4.1 BA1/BS1/PM2_supporting +# Variant universe: all gnomAD v4.1 PASS variants in the 8 gene CDS regions +# +/- 20 nt splice padding. fetch_gene_variants() is the canonical universe, +# reused by B.6 and B.11. +# Output: 10,974 features. Applied code: PM2_supporting 9,893, no-code 504, +# BS1 367, BA1 210. MYBPC3 BS1 outlier (0.0002) handled per gene. +# +# B.6 cmpVCEPAnnotate.py — hgVai consequence + HGVSp annotation layer +# Reuses B.3 fetch_gene_variants() for an identical universe, then runs +# hgVai per gene via vai.pl on the single MANE Select transcript: +# vai.pl --variantLimit=200000000 --hgVai=/usr/local/apache/cgi-bin/hgVai \ +# --position=<chrom>:<txStart>-<txEnd> --geneTrack=ncbiRefSeqSelect \ +# --hgvsG=off --hgvsCN=off --hgvsP=on hg38 <variants.vcf.gz> +# Each input VCF row carries ID=chrom:pos:ref:alt so indels join exactly on +# the way back (without the ID, VEP reformats indel names and ~659 fail to +# join). Output cmpVCEPAnnotate/cmpVCEPAnnotations.hg38.tsv: 10,974 rows, +# 0 unmapped. Columns: chrom,pos,ref,alt,gene,soTerms,proteinPos,aaRef,aaAlt, +# codonChange,exonNum,exonTotal,cdnaPos,hgvsp. Feeds PS1/PM5/PM4/BP7 in B.11. +# (ncbiRefSeqSelect = single MANE transcript per gene; an intentional +# divergence from the evaSnp ncbiRefSeqCurated default — correct for a +# curated 8-gene panel. hg38 only; codes carry to hg19 with the variant +# universe via the per-track liftOver.) +# +# B.4 cmpVCEPRevel.py — REVEL PP3/BP4 thresholded scores +# Output: 22,466 features. REVEL >= 0.70 -> PP3_supporting; <= 0.40 -> +# BP4_supporting; in-between dropped (nothing drawn). fetch_revel_bedgraph() +# splits multi-bp bedGraph runs into 1-bp per-alt records (each position has +# its own REF allele). +# +# B.5 cmpVCEPCardioBoost.py — CardioBoost missense predictor (informational) +# Loads cm_prediction.RData via /usr/bin/Rscript; 31,236 missense predictions +# across the 8 genes. GRCh37 native -> add chr prefix -> liftOver to hg38 +# (0 unmapped). Rendered as a default-OFF subtrack under the Bioinformatic +# composite (sibling to REVEL). Colored by CardioBoost's own published class +# (probability >= 0.9 Pathogenic, <= 0.1 Benign, else Indeterminate). NOT a +# CSpec-specified predictor and fires no ACMG code — informational only. +# name field includes ref/alt so same-aa variants via different nt are unique. +# +# B.7 cmpVCEPEvRepo.py — VCEP Curated Variants from EvRepo (Final, with codes) +# Output: 25 features (all MYH7). The complex repeat-notation p.Glu931del +# (c.2785GAG[2]) is recovered via a coords_via_hgvstovcf() fallback. +# Mouseover prefix "Final — VCEP EvRepo submission"; codesMet filtered to +# status="Met"; codesAll = Met + NotMet where enumerated. Standard 5-tier +# ACMG ramp. +# +# B.7c cmpVCEPWalsh2019.py — Walsh 2019 Pre-EvRepo curations (Table S6) +# Output: 155 features (3 rows outside our 8 genes filtered out). All 155 +# are rendered: the 32 previously unmatched-to-ClinVar entries (complex +# indels + 4 TNNT2 SNVs incl. R92W) are placed via walsh_coords_via_tool() +# = hgvsToVcf on each gene's Walsh-paper transcript, gated on FILTER==PASS. +# TNNT2 uses NM_001001430.2 (MANE gives HgvsRefAssertedMismatch); TNNT2 hg19 +# coords via liftOver from hg38. 27 variants tagged "Walsh-upgraded" (the new +# PM1 EF rule, asterisked in Table S6). Classification strings normalized to +# "Uncertain Significance" (not "VUS"). Standard ACMG ramp. +# +# B.8 cmpVCEPClinVar506161.py — VCEP ClinVar submissions (Final, no codes) +# Output: 199 features. Joined to variant_summary for hg38 + hg19 coords. +# All carry review status "reviewed by expert panel". 25 of 199 overlap +# EvRepo (flagged inline in the mouseover). Standard 5-tier ACMG ramp (the +# earlier desaturated palette was dropped). Carries no per-code evidence. +# +# B.9 cmpVCEPWalshOR.py — Walsh 2017 gene-level case-control OR (PS4) +# Source: Walsh 2017 Supplementary_Tables_resubmit.xlsx, Tables S5A (HCM) / +# S5B (DCM). Output: 48 features = 8 genes x {HCM, DCM} x {All protein- +# altering, Truncating, Non-truncating}, each spanning the gene CDS (MANE), +# filterable by gene / cohortDisease / variantClass / ps4Strength. +# PS4 strength by OR 95%-CI lower bound (Strong >=20, Moderate >=10, +# Supporting >=5, else below threshold): Strong 1, Moderate 7, Supporting 9, +# below threshold 31. Standout: MYBPC3 truncating-HCM OR 118.8 (86.1-163.9) +# -> Strong. hg38 from MANE CDS; hg19 via liftOver. Replaces the earlier +# Walsh-2019 EF table (a different statistic; per CSpec, PS4 cites Walsh 2017). +# +# B.10 cmpVCEPAtlasEF.py — Atlas per-variant case-counts + UCSC-computed OR (PS4) +# Source: cmp_downloads/atlas/variants/var_*.html (173 parsed; 16 parse +# failures). Output: 178 features (a variant renders once per disease cohort +# where it has data). UCSC computes the OR (Fisher 2x2 with Haldane 0.5 +# correction; Woolf log-OR 95% CI) from Atlas case counts against ExAC +# controls; per-gene Walsh-2019 NonTrunc ExAC denominators are used for +# non-truncating vartypes, else the 60,706 baseline. PS4 strength binning: +# Strong 16, Moderate 30, Supporting 44, below threshold 88. Every mouseover +# carries the caveat that the OR is UCSC-computed against ExAC (not gnomAD). +# +# B.11 cmpVCEPProvisionalClass.py — NON-FINAL Provisional Classification +# Variant universe: identical to B.3 (10,974). Consumes the B.6 annotation +# TSV. Computable codes applied: BA1/BS1/PM2_supporting (B.3 FAF95), +# PP3/BP4 (REVEL, missense), PM1 (CSpec hotspot region), PS1/PM5 (EvRepo +# P/LP reference, leave-one-out — a variant cannot earn the code from its +# own entry; PS1 reference excludes established splice-impact variants e.g. +# MYBPC3 c.2308G>A), PM4 (NMD-escaping truncating, non-MYBPC3: last exon or +# within 50 nt of the final exon-exon junction), BP7 (synonymous + +# SpliceAI < 0.20 + phyloP470way <= 0). +# Combination rules = CSpec GN002 verbatim (NOT Tavtigian point sums; PP2 +# is not in the GN002 point system and is not emitted). PM1<->PM5 mutual +# exclusion enforced per CSpec (keep PM5, the variant-specific code; drop +# PM1; PM1+PS1 co-occurrence flagged). BS1-standalone -> Likely Benign per +# the GN002 BS1 carve-out. SpliceAI safety net runs last (>= 0.20 on an +# LB/B call -> VUS). HCM/DCM diseaseTag populated. +# The mockup omits all clinical/functional codes (PS2/PS3/PS4/PP1/PP4/ +# BS3/BS4), so it structurally cannot reach Pathogenic/Likely Pathogenic; +# this is intentional and labeled NON-FINAL throughout (BED name, .as, +# trackDb, mouseover, description page). No concordance metric is asserted. +# Output: 10,974 features — 0 P / 0 LP / 10,453 VUS / 319 LB / 202 B. + + +############################################################################## +# Phase C: Hub assembly +############################################################################## +# +# Files written/maintained by hand (NOT generated by the build scripts): +# hub.txt, genomes.txt +# cardiomyopathy.html (shared description page; hub descriptionUrl) +# hg38/trackDb.txt +# hg19/trackDb.txt (mirrors hg38; differs in bigDataUrl + an hg19 +# provenance header noting liftOver-derived coords) +# +# trackDb structure: 7 top-level groups -> 11 tracks. Three are composites: +# Bioinformatic (REVEL on + CardioBoost off), VCEP Curated Variants (EvRepo on +# + ClinVar off + Walsh 2019 off), PS4 Case-Control (Walsh OR on + Atlas EF off). +# bigBed filterValues on the ACMG-code / ps4Strength fields; default visibility +# tuned so the first view is clean (dense for the big per-variant tracks). +# +# Validation: +# hubCheck https://hgwdev.gi.ucsc.edu/~lrnassar/track_hubs/cardiomyopathyVCEP/hub.txt +# +# Web access (sandbox; working dir served directly via symlink): +# ln -sf /hive/users/lrnassar/claude/RM37446 \ +# /cluster/home/lrnassar/public_html/track_hubs/cardiomyopathyVCEP +# Hub URL: https://hgwdev.gi.ucsc.edu/~lrnassar/track_hubs/cardiomyopathyVCEP/hub.txt + + +############################################################################## +# Phase D: Verification +############################################################################## +# +# (Build verification only. QA history, audit findings, and review/release +# readiness are tracked in Redmine #37446, not here.) +# +# - hubCheck: silent pass (exit 0) on hg38 + hg19. +# - Cross-assembly parity (hg38 == hg19 feature counts): +# PM1 28 | PVS1 16 | AF 10,974 | REVEL 22,466 | EvRepo 25 | Walsh2019 155 | +# ClinVar 199 | WalshOR 48 | AtlasEF 178 | Provisional 10,974 | +# CardioBoost 31,236 +# - Worked example, MYH7 p.Arg870His (NM_000257.4:c.2609G>A, chr14:23424839 hg38): +# EvRepo: Pathogenic, codes PM1;PM2;PP1_Strong;PS4 +# EvRepo R870C: Likely Pathogenic at the adjacent codon-870 position +# (the PS1/PM5 partner) +# PM1: within MYH7 167-931 +# REVEL: 0.853 -> PP3_supporting +# gnomAD AF: absent from v4.1 exomes -> PM2_supporting +# Walsh OR: MYH7 non-truncating HCM, OR 12.0 (10.9-13.3) -> Moderate +# Provisional: Uncertain Significance (PM1+PM2+PP3, no clinical PS4/PP1 -> +# no P/LP rule fires) — the expected under-call + + +############################################################################## +# Phase E: Otto cron (TODO — gated on VCEP sign-off; do AFTER deployment) +############################################################################## +# +# DO NOT enable until the VCEP signs off (Phase F gate). The weekly refresh +# touches EvRepo + ClinVar 506161 only; premature activation could surface +# unreviewed VCEP curations on the public hub. +# +# Mirror the TP53 pattern at /hive/data/outside/otto/cardiomyopathyVCEP/ +# (doUpdate.sh + checkCMPVCEPClinVar.sh). Crontab (NOT activated until sign-off): +# # Cardiomyopathy VCEP weekly EvRepo + ClinVar update +# 2x 03 * * 2 umask 002; /hive/data/outside/otto/cardiomyopathyVCEP/doUpdate.sh +# Tuesday ~03:2x UTC — offset a few minutes from TP53 (03:15) and InSiGHT (03:10). + + +############################################################################## +# Phase F: Deployment to hgdownload (TODO — gated on VCEP expert review) +############################################################################## +# +# Steps: +# 1. (Done) MYH7 draft sent to Haley Garrett / Lucas Bronicki with a shared +# hgwdev session + interpretation questions. +# 2. After sign-off, decide the NON-FINAL Provisional track's fate (keep as a +# labeled mockup vs drop) per VCEP feedback. +# 3. Symlink hub into hgdownload and coordinate autoPush: +# ln -sf /hive/users/lrnassar/claude/RM37446 \ +# /usr/local/apache/htdocs-hgdownload/hubs/cardiomyopathyVCEP +# Public URL: https://hgdownload.soe.ucsc.edu/hubs/cardiomyopathyVCEP/hub.txt +# 4. Commit to git (per CLAUDE.md, `refs #37446`): +# - This file -> ~/kent/src/hg/makeDb/doc/Cardiomyopathy.txt +# - All 12 build scripts -> ~/kent/src/hg/makeDb/scripts/cardiomyopathyVCEP/ +# Then verify the cardiomyopathy.html GitHub "source code" links resolve and +# remove the PLACEHOLDER caveat; run encodeEmail.pl (already applied) and +# switch the Data Access section to the hgdownload (TP53-style) wording. + + +############################################################################## +# Phase G: Recommended Track Set (TODO — after Phase E activation) +############################################################################## +# +# Create RTS sessions on dev (hgSession) for hg38 and hg19 with the hub loaded +# at default subtrack visibility. Save under the VCEP folder alongside InSiGHT +# and TP53. + + +############################################################################## +# Phase H: Folder taxonomy (DEFERRED — until a 4th VCEP hub exists) +############################################################################## +# +# With InSiGHT + TP53 + Cardiomyopathy = 3 VCEP hubs, propose an RTS folder +# structure when a 4th hub lands. Matches the TP53 makedoc Phase H deferral. + + +############################################################################## +# References +############################################################################## +# +# Walsh R, Thomson KL, et al. (2017). Reassessment of Mendelian gene +# pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference +# samples. Genet Med. PMID 27532257; DOI 10.1038/gim.2016.90. +# +# Walsh R, Mazzarotto F, et al. (2019). Quantitative approaches to variant +# classification increase the yield and precision of genetic testing in +# Mendelian diseases: the case of hypertrophic cardiomyopathy. +# Genome Medicine. PMID 30696458; DOI 10.1186/s13073-019-0616-z. +# +# Kelly MA, Caleshu C, et al. (2018). Adaptation and validation of the +# ACMG/AMP variant classification framework for MYH7-associated inherited +# cardiomyopathies. Genet Med. PMID 29300372. +# +# Jordan E, Peterson L, et al. (2021). Evidence-based assessment of genes +# in dilated cardiomyopathy. Circulation. PMID 33947203. +# +# Zhang X, Walsh R, et al. (2021). Disease-specific variant pathogenicity +# prediction significantly improves variant interpretation in inherited +# cardiac conditions (CardioBoost). Genome Medicine. PMID 33420041. +# +# Richards S, Aziz N, et al. (2015). Standards and guidelines for the +# interpretation of sequence variants. Genet Med. PMID 25741868. +# +# Remaining/deferred work is tracked in Redmine #37446 and +# memory/rm37446_v2_punchlist.md (not duplicated here).