variant-report

name	variant-report
description	Generate a variant annotation report combining Ensembl, ClinVar, and UniProt data for a gene or genomic region

Generate a comprehensive variant annotation report for: $ARGUMENTS

Use the MCP tools available to you to gather variant data from all relevant sources, then synthesize a single structured report. Follow the steps below. If a step fails, note the gap and continue.

Determine Input Type

First, classify the input:

• Gene symbol (e.g., TP53, BRCA1): Look up genomic coordinates first, then find variants in that region.
• Genomic region (e.g., 7:140453136-140453236): Use directly for variant lookup.
• Specific variant (e.g., NM_007294.4:c.5266dupC or rs ID): Search ClinVar directly.

Data Gathering Steps

For Gene Symbol Input:

1. Gene Coordinates

• Call ensembl_lookup_gene with the gene symbol to get chromosomal coordinates.
• Note the chr:start-end for variant queries.

2. Known Variants in the Region

• Call ensembl_get_variants with the gene's region (species: homo_sapiens, limit: 100).
• Summarize: total variants found, breakdown by consequence type, any with clinical significance.

3. ClinVar Annotations

• Call clinvar_search with the gene symbol (limit: 20) to get clinical interpretations.
• Call clinvar_search with "[gene] AND pathogenic" to specifically find pathogenic variants.
• Summarize: total entries, breakdown by clinical significance (pathogenic, likely pathogenic, VUS, benign).

4. Protein Feature Context

• Call uniprot_search with the gene symbol and organism_id:9606 (reviewed: true) to find the UniProt accession.
• Call uniprot_get_features with the accession to get domain boundaries and functional sites.
• This gives context for interpreting which variants fall in functionally important regions.

5. Protein Sequence (for reference)

• Call ensembl_get_sequence with the Ensembl gene ID (seq_type: protein) to get the protein sequence length for position mapping context.

For Genomic Region Input:

Follow steps 2-4 above, using the provided region directly. For step 3, search ClinVar with the region or nearby gene name.

For Specific Variant Input:

1. ClinVar Lookup

• Call clinvar_search with the exact variant description.
• Extract clinical significance, review status, associated conditions, and supporting evidence count.

2. Gene Context

• From the ClinVar result, identify the gene. Then call ensembl_lookup_gene to get full gene context.
• Call uniprot_get_features to see if the variant falls in a known functional domain.

Report Format

Present the report with these sections:

# Variant Report: [TARGET]

## Summary
One-paragraph overview: what gene/region this covers, key clinical findings, and notable variants.

## Gene / Region Context
- Gene symbol, Ensembl ID, chromosomal location
- Gene function (brief, from prior lookup)
- Protein length and key domains

## Variant Landscape
- Total known variants in the region (from Ensembl)
- Breakdown by consequence type (missense, synonymous, frameshift, etc.)
- Variants with clinical significance annotations

## Clinical Significance (ClinVar)
- Total ClinVar entries for this gene/region
- Breakdown: Pathogenic | Likely Pathogenic | VUS | Likely Benign | Benign
- Top pathogenic variants (up to 10):
  | Variant | Clinical Significance | Condition(s) | Review Status |
  |---------|----------------------|---------------|---------------|
  | ...     | ...                  | ...           | ...           |

## Protein Domain Context
- Domain map showing where key variants fall relative to functional domains
- Highlight variants in active sites, binding domains, or known hotspots

## Interpretation Notes
- Which regions of this gene are most clinically relevant
- Any variant hotspots (clusters of pathogenic variants)
- Note if certain domains are enriched for pathogenic variants

## Data Sources
List which databases were queried and whether each returned data successfully.

Keep the report factual — only include data returned by the tools. Do not hallucinate variant interpretations. If clinical significance is uncertain (VUS), state that clearly. If a section has no data, write "No data available from [source]."