ClinGen Pathogenicity Calculator

ClinGen Pathogenicity Calculator standardizes interpretation of Mendelian germline sequence variants by applying the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) evidence-based criteria to allele-specific evidence tags; it was developed by the Clinical Genome Resource (ClinGen).

Key Features:

• Guideline-Based Assessment: Applies ACMG/AMP-style evidence tags to alleles and links each tag to supporting data to produce guideline-compliant pathogenicity evaluations.
• Automated Rule Application: Automates combination of evidence codes according to ACMG/AMP criteria to generate provisional pathogenicity classifications.
• Configurable Rules of Reasoning: Supports gene-specific and disease-specific configurations, including cardiomyopathy-specific allele frequency thresholds and functional assay criteria.
• APIs and Modular Integration: Exposes application program interfaces (APIs) for modular integration with variant curation systems and computational pipelines.

Scientific Applications:

• Clinical Variant Classification: Provides standardized pathogenicity classifications for Mendelian germline sequence variants to support clinical genomics.
• Resolution of Discordant Interpretations: Enables collaborative evidence evaluation workflows to reconcile discordant variant interpretations across laboratories and databases.
• Gene- and Assay-Specific Interpretation: Incorporates gene-specific rules and functional assay criteria to inform genetic diagnosis and research on variant effects.

Methodology:

ACMG/AMP-style evidence tags for sequence variants (alleles) are entered and processed according to American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to combine evidence codes into pathogenicity assessments.