Genomics

Interpret genomic variants with ACMG classification, pharmacogenomics, and clinical annotation from ClinVar and gnomAD.

Setup

On first use, read setup.md for integration guidelines. Ask user consent before creating ~/genomics/ workspace.

When to Use

User has processed genomic data (VCF files) and needs clinical interpretation. Agent handles variant classification, pharmacogenomics recommendations, and annotation lookup. NOT for raw data processing — use bioinformatics skill for alignment and variant calling.

Architecture

Memory lives in ~/genomics/. See memory-template.md for structure.

text

~/genomics/
├── memory.md           # Context + preferences + interpretation history
└── cases/              # Active interpretation cases

Quick Reference

Topic	File
Setup process	setup.md
Memory template	memory-template.md

Core Rules

1. Classify Variants Using ACMG Guidelines

Every variant needs systematic classification:

Category	Criteria
Pathogenic	PVS1, PS1-4, PM1-6, PP1-5 weighted
Likely Pathogenic	Strong + moderate evidence
VUS	Insufficient or conflicting evidence
Likely Benign	BS1-4, BP1-7 weighted
Benign	Strong benign evidence

Never classify without evidence. State "insufficient data" when appropriate.

2. Check Population Frequency First

Before clinical interpretation, verify frequency:

Source	Use For
gnomAD v4	Global population frequency
gnomAD non-cancer	Somatic analysis
Population-specific	Ancestry-appropriate filtering

MAF >1% in any population = likely benign for rare disease.

3. Cross-Reference Multiple Databases

Database	Information
ClinVar	Clinical classifications + submitter evidence
OMIM	Gene-disease relationships
HGMD	Literature-reported mutations
UniProt	Protein function + domains

Single-source interpretation is insufficient. Triangulate evidence.

4. Report Pharmacogenomics Actionably

For drug-gene interactions, provide:

• Diplotype (e.g., CYP2D6 *1/*4)
• Predicted phenotype (poor/intermediate/normal/ultra-rapid metabolizer)
• Drug list affected
• Dosing guidance (CPIC/DPWG when available)

5. Separate Germline from Somatic Context

Context	Key Differences
Germline	Family implications, carrier testing, predictive
Somatic	Tumor-specific, therapy selection, no inheritance

Always state which context you're interpreting.

6. Acknowledge Uncertainty

• Novel variants often lack evidence
• VUS ≠ benign — requires ongoing monitoring
• Reclassification happens (ClinVar updates monthly)
• Computational predictions are supportive, not definitive

Pharmacogenomics Reference

High-Priority Drug-Gene Pairs (CPIC Level A)

Gene	Drugs	Clinical Action
CYP2D6	Codeine, tramadol, tamoxifen, SSRIs	Dosing/alternative
CYP2C19	Clopidogrel, PPIs, voriconazole	Dosing/alternative
CYP2C9 + VKORC1	Warfarin	Dosing algorithm
DPYD	Fluorouracil, capecitabine	Dose reduction/avoid
TPMT + NUDT15	Azathioprine, mercaptopurine	Dose reduction
HLA-B*57:01	Abacavir	Contraindication
HLA-B*15:02	Carbamazepine	Contraindication (Asian ancestry)
SLCO1B1	Simvastatin	Dose cap/alternative statin
G6PD	Rasburicase, primaquine	Contraindication
CYP3A5	Tacrolimus	Dosing adjustment

Phenotype Interpretation

Metabolizer Status	Meaning	Typical Action
Poor (PM)	Little/no enzyme activity	Alternative drug or dose ↓↓
Intermediate (IM)	Reduced activity	Consider dose ↓
Normal (NM)	Expected activity	Standard dosing
Rapid/Ultra-rapid (UM)	Increased activity	Dose ↑ or alternative

Annotation Resources

Resource	URL	Content
ClinVar	ncbi.nlm.nih.gov/clinvar	Clinical variant classifications
gnomAD	gnomad.broadinstitute.org	Population frequencies
OMIM	omim.org	Gene-disease relationships
PharmGKB	pharmgkb.org	Drug-gene annotations
CPIC	cpicpgx.org	Pharmacogenomics guidelines
ClinGen	clinicalgenome.org	Gene-disease validity
Franklin	franklin.genoox.com	Variant interpretation aid
VarSome	varsome.com	ACMG auto-classification

Common Interpretation Traps

• Ignoring population specificity — Variants common in African populations may look rare in European-biased databases
• Trusting single ClinVar submitter — Check submitter count and review status (≥2 submitters, no conflict preferred)
• Conflating computational prediction with evidence — CADD/REVEL are supportive, not diagnostic
• Missing compound heterozygosity — Two VUS in trans can be pathogenic together
• Outdated database versions — gnomAD v4 has 800K+ exomes vs v2's 125K
• Ignoring gene-level constraint — pLI/LOEUF scores indicate tolerance to loss-of-function

External Endpoints

This skill does NOT automatically call external APIs. All database references are for manual lookup:

Resource	When Used	Data Sent
ClinVar, gnomAD, OMIM	User manually visits	None by this skill
PharmGKB, CPIC	User manually visits	None by this skill
VarSome, Franklin	User manually visits	None by this skill

No automatic network requests. The skill provides URLs and guidance for manual lookup only.

Security & Privacy

Data that stays local:

• All interpretation work runs locally
• No variant data sent externally by this skill
• No automatic API calls to any database

This skill does NOT:

• Make network requests automatically
• Upload patient variants anywhere
• Connect to databases without explicit user action
• Store identifiable genomic information outside ~/genomics/

Related Skills

Install with clawhub install <slug> if user confirms:

• medicine — clinical decision support
• biology — molecular mechanisms
• chemistry — drug metabolism pathways
• health — patient care context

Feedback

• If useful: clawhub star genomics
• Stay updated: clawhub sync