genome-variant-annotation

Skill: genome-variant-annotation

Use When

• User wants to annotate variants with gene and transcript impact predictions.
• User needs to predict functional consequences (missense, nonsense, splice-site, etc.).
• User wants to add population allele frequencies (gnomAD, 1000 Genomes).
• User wants to add clinical annotations (ClinVar significance).
• User needs to compare annotation engines (SnpEff vs VEP).

Inputs

• Required:
  • Filtered VCF file (.vcf.gz).
• Optional:
  • Annotator choice: snpeff or vep (default: snpeff).
  • Genome build (default: GRCh38).
  • Cache directory for annotation databases.
  • Additional VEP plugins or fields (e.g., CADD, LOFTEE).
  • Output format (default: VCF).

Workflow

1. If SnpEff: run snpEff ann with the appropriate database (e.g., GRCh38.105), producing an annotated VCF and summary stats HTML.
2. If VEP: run vep with --cache, --merged or --refseq, and add plugins (CADD, gnomAD, ClinVar, LOFTEE).
3. Add fields to each variant: gene symbol, consequence, impact tier (HIGH / MODERATE / LOW / MODIFIER), HGVS notation.
4. Optionally add population allele frequencies from gnomAD.
5. Generate summary statistics: variants by impact category, genes with HIGH-impact variants.

Output Contract

• Annotated VCF file (.vcf.gz).
• Annotation summary: HTML report (SnpEff) or stats file (VEP).
• Variant impact distribution (HIGH, MODERATE, LOW, MODIFIER counts).

Limits

• SnpEff and VEP annotation databases must be pre-downloaded to the cache directory.
• VEP plugins (CADD, LOFTEE, gnomAD) require separate data file downloads.
• Annotation databases must match the reference genome build (GRCh37 vs GRCh38).
• VEP is generally slower but more configurable than SnpEff.
• Large VCFs (millions of variants) may require significant memory and runtime.
• Common failure cases:
  • SnpEff database name not matching the reference build (e.g., using hg19 when VCF is on GRCh38).
  • VEP cache directory missing or not matching the installed VEP version.
  • VEP plugin data files (CADD, LOFTEE) not downloaded or path misconfigured.