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Clinical Interpretation Usage Guide

Overview

Prioritize and classify variants for clinical significance using ClinVar annotations, population frequencies, and ACMG classification guidelines.

Prerequisites

# InterVar for ACMG classification
pip install intervar

# ClinVar database
wget ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar.vcf.gz

Interpretation Framework

Annotated VCF
    ├── ClinVar lookup (known clinical assertions)
    ├── Population frequency (gnomAD)
    ├── Computational predictions (SIFT, PolyPhen, CADD)
    ├── ACMG classification
    └── Prioritized variant list

Quick Start

Add ClinVar Annotations

bcftools annotate \
    -a clinvar.vcf.gz \
    -c INFO/CLNSIG,INFO/CLNDN \
    input.vcf.gz -Oz -o with_clinvar.vcf.gz

Filter Clinically Relevant

from cyvcf2 import VCF

for v in VCF('annotated.vcf.gz'):
    clnsig = v.INFO.get('CLNSIG', '')
    if 'Pathogenic' in clnsig or 'Likely_pathogenic' in clnsig:
        print(f'{v.CHROM}:{v.POS} {v.REF}>{v.ALT[0]} - {clnsig}')

ACMG Classification

The 5-tier system for variant pathogenicity:

Class Meaning Action
Pathogenic Disease-causing Report, clinical action
Likely pathogenic Probably disease-causing Report, consider action
VUS Uncertain significance Report with caution
Likely benign Probably not disease-causing May report
Benign Not disease-causing Usually not reported

Prioritization Criteria

def prioritize_variant(v):
    score = 0

    # ClinVar pathogenic
    if 'Pathogenic' in v.INFO.get('CLNSIG', ''):
        score += 10

    # Rare in gnomAD
    af = v.INFO.get('gnomAD_AF', 1.0)
    if af < 0.001:
        score += 5

    # High CADD score
    cadd = v.INFO.get('CADD_PHRED', 0)
    if cadd > 20:
        score += 3

    # Protein-altering
    if 'missense' in v.INFO.get('Consequence', ''):
        score += 2

    return score

Key Databases

Database Purpose
ClinVar Clinical variant assertions
gnomAD Population allele frequencies
OMIM Disease-gene associations
CADD Deleteriousness scores

Reporting Considerations

  • Always include variant evidence and classification rationale
  • VUS variants may be reclassified with new evidence
  • Consider family segregation data when available
  • Follow laboratory/institutional reporting guidelines

Example Prompts

"Annotate my VCF with ClinVar clinical significance"

"Filter for pathogenic and likely pathogenic variants"

"Prioritize variants by clinical relevance"

"Apply ACMG classification criteria to my variants"

Tips

  • Always include variant evidence and classification rationale
  • VUS variants may be reclassified with new evidence
  • Consider family segregation data when available
  • Follow laboratory/institutional reporting guidelines

See Also