Structural Variant Analysis Workflow

Systematic analysis of structural variants (deletions, duplications, inversions, translocations, complex rearrangements) for clinical genomics interpretation using ACMG-adapted criteria.

KEY PRINCIPLES

:

Report-first approach

- Create SV_analysis_report.md FIRST, then populate progressively

ACMG-style classification

- Pathogenic/Likely Pathogenic/VUS/Likely Benign/Benign with explicit evidence

Evidence grading

- Grade all findings by confidence level (High/Moderate/Limited)

Dosage sensitivity critical

- Gene dosage effects drive SV pathogenicity

Breakpoint precision matters

- Exact gene disruption vs dosage-only effects

Population context essential

- gnomAD SVs for frequency assessment

English-first queries

- Always use English terms in tool calls (gene names, disease names), even if the user writes in another language. Only try original-language terms as a fallback. Respond in the user's language

Triggers

Use this skill when users:

Ask about structural variant interpretation

Have CNV data from array or sequencing

Ask "is this deletion/duplication pathogenic?"

Need ACMG classification for SVs

Want to assess gene dosage effects

Ask about chromosomal rearrangements

Have large-scale genomic alterations requiring interpretation

Workflow Overview

Phase 1: SV IDENTITY & CLASSIFICATION

Normalize coordinates (hg19/hg38), determine type (DEL/DUP/INV/TRA/CPX),

calculate size, assess breakpoint precision

Phase 2: GENE CONTENT ANALYSIS

Identify fully contained genes, partially disrupted genes (breakpoint within),

flanking genes (within 1 Mb), annotate function and disease associations

Phase 3: DOSAGE SENSITIVITY ASSESSMENT

ClinGen HI/TS scores, pLI scores, OMIM inheritance patterns,

gene-disease validity levels

Phase 4: POPULATION FREQUENCY CONTEXT

gnomAD SV database, ClinVar known SVs, DECIPHER patient cases,

reciprocal overlap calculation (>=70% = same SV)

Phase 5: PATHOGENICITY SCORING

Quantitative 0-10 scale: gene content (40%), dosage sensitivity (30%),

population frequency (20%), clinical evidence (10%)

Phase 6: LITERATURE & CLINICAL EVIDENCE

PubMed searches, DECIPHER cohort analysis, functional evidence

Phase 7: ACMG-ADAPTED CLASSIFICATION

Apply SV-specific evidence codes, calculate final classification,

generate clinical recommendations

Phase 1: SV Identity & Classification

Goal

Standardize SV notation and classify type.

Capture: chromosome(s), coordinates (start/end in hg19/hg38), SV size, SV type (DEL/DUP/INV/TRA/CPX), breakpoint precision, inheritance pattern (de novo/inherited/unknown).

For SV type definitions, scoring tables, and ACMG code details, see

CLASSIFICATION_GUIDE.md

.

Phase 2: Gene Content Analysis

Goal

Annotate all genes affected by the SV.

Tools

:

Tool

Purpose

Ensembl_lookup_gene

Gene structure, coordinates, exons

NCBI_gene_search

Official symbol, aliases, description

Gene_Ontology_get_term_info

Biological process, molecular function

OMIM_search

,

OMIM_get_entry

Disease associations, inheritance

DisGeNET_search_gene

Gene-disease association scores

Classify genes as:

fully contained

(entire gene in SV),

partially disrupted

(breakpoint within gene), or

flanking

(within 1 Mb of breakpoints).

For implementation pseudocode, see

ANALYSIS_PROCEDURES.md

Phase 2.

Phase 3: Dosage Sensitivity Assessment

Goal

Determine if affected genes are dosage-sensitive.

Tools

:

Tool

Purpose

ClinGen_search_dosage_sensitivity

HI/TS scores (0-3, gold standard)

ClinGen_search_gene_validity

Gene-disease validity level

gnomad_search

pLI scores for LoF intolerance

DECIPHER_search

Developmental disorder cases

OMIM_get_entry

Inheritance pattern (AD suggests dosage sensitivity)

Key thresholds: ClinGen HI/TS score 3 = definitive dosage sensitivity. pLI >= 0.9 = likely haploinsufficient. See

CLASSIFICATION_GUIDE.md

for full score interpretation tables.

Phase 4: Population Frequency Context

Goal

Determine if SV is common (likely benign) or rare (supports pathogenicity).

Tools

:

Tool

Purpose

gnomad_search

Population SV frequencies

ClinVar_search_variants

Known pathogenic/benign SVs

DECIPHER_search

Patient SVs with phenotypes

Key thresholds: >=1% = BA1 (benign). 0.1-1% = BS1 (strong benign). <0.01% = PM2 (supporting pathogenic). Use >=70% reciprocal overlap to define "same" SV.

Phase 5: Pathogenicity Scoring

Goal

Quantitative pathogenicity assessment on 0-10 scale.

Four components weighted: gene content (40%), dosage sensitivity (30%), population frequency (20%), clinical evidence (10%).

Score mapping: 9-10 = Pathogenic, 7-8 = Likely Pathogenic, 4-6 = VUS, 2-3 = Likely Benign, 0-1 = Benign.

For detailed scoring breakdowns and implementation, see

CLASSIFICATION_GUIDE.md

and

ANALYSIS_PROCEDURES.md

Phase 5.

Phase 6: Literature & Clinical Evidence

Goal

Find case reports, functional studies, and clinical validation.
Tools
:
Tool
Purpose
PubMed_search
Peer-reviewed literature
EuropePMC_search
European literature (additional coverage)
DECIPHER_search
Patient case database
Search strategies: gene-specific dosage sensitivity papers, SV-specific case reports, DECIPHER cohort phenotype analysis. See
ANALYSIS_PROCEDURES.md
Phase 6.
Phase 7: ACMG-Adapted Classification
Goal: Apply ACMG/ClinGen criteria adapted for SVs. Key pathogenic codes: PVS1 (deletion of HI gene), PS1 (matches known pathogenic SV), PS2 (de novo), PM2 (absent from controls), PP4 (phenotype match). Key benign codes: BA1 (MAF >5%), BS1 (MAF >1%), BS3 (no functional effect). Classification rules: Pathogenic = PVS1+PS1 or 2 Strong. Likely Pathogenic = 1 Very Strong + 1 Moderate, or 3 Moderate. VUS = criteria not met. Likely Benign = 1 Strong + 1 Supporting. Benign = BA1, or 2 Strong benign. For complete evidence code tables and classification algorithm, see CLASSIFICATION_GUIDE.md . Output Create report using the template in REPORT_TEMPLATE.md . Name files as: SV_analysis_[TYPE]chr[CHR][START][END][GENES].md Quantified Minimums Section Requirement Gene content All genes in SV region annotated Dosage sensitivity ClinGen scores for all genes (if available) Population frequency Check gnomAD SV + ClinVar + DGV Literature search

=2 search strategies (PubMed + DECIPHER) ACMG codes All applicable codes listed Tools Reference Tool Purpose Required? ClinGen_search_dosage_sensitivity HI/TS scores Required ClinGen_search_gene_validity Gene-disease validity Required ClinVar_search_variants Known pathogenic/benign SVs Required DECIPHER_search Patient cases, phenotypes Highly recommended Ensembl_lookup_gene Gene coordinates, structure Required OMIM_search , OMIM_get_entry Gene-disease associations Required DisGeNET_search_gene Additional disease associations Recommended PubMed_search Literature evidence Recommended Gene_Ontology_get_term_info Gene function Supporting When NOT to Use This Skill Single nucleotide variants (SNVs) - Use tooluniverse-variant-interpretation Small indels (<50 bp) - Use variant interpretation skill Somatic variants in cancer - Different framework needed Mitochondrial variants - Specialized interpretation required Repeat expansions - Different mechanism Use this skill for structural variants >=50 bp requiring dosage sensitivity assessment and ACMG-adapted classification. Reference Files EXAMPLES.md - Sample SV interpretations with worked examples CLASSIFICATION_GUIDE.md - ACMG criteria tables, scoring system, evidence codes, special scenarios, clinical recommendations REPORT_TEMPLATE.md - Full report template with section structure and file naming ANALYSIS_PROCEDURES.md - Detailed implementation pseudocode for each phase External References ClinGen Dosage Sensitivity Map: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/ ACMG SV Guidelines: Riggs et al., Genet Med 2020 (PMID: 31690835) tooluniverse-variant-interpretation - For SNVs and small indels

tooluniverse-structural-variant-analysis

安装