Documentation / Reference Databases / ClinGen

ClinGen

ClinGen provides expert-curated haploinsufficiency and triplosensitivity assessments. Folklore uses these records as gene-level evidence in nuclear classification and screening, and as dosage-sensitivity evidence in the constitutional SV/CNV workflow.

Database Details

Sourceclinicalgenome.org

ProducerClinGen Consortium (NIH-funded)

Role in ACMG Classification

For nuclear SNV and indel classification, selected dosage fields contribute gene-level inheritance and mechanism context:

BS1Strong Benign

Haploinsufficiency score = 3 is used as a proxy for autosomal dominant inheritance. When triggered, BS1 applies a stricter frequency threshold (AF >= 0.1%) compared to the default recessive threshold (AF >= 5%).

BP2Supporting Benign

When a variant is a compound heterozygote candidate and ClinGen haploinsufficiency score = 30 (dosage sensitivity unlikely), BP2 applies. This combination suggests the variant is less likely to be pathogenic in a dominant context.

Columns Loaded (2)

ClinGen data is joined on gene symbol. Each variant inherits its gene-level dosage sensitivity scores.

haploinsufficiency_scoreINTEGER

Haploinsufficiency assessment score. Values 0-3 indicate evidence level for haploinsufficiency. Special values: 30 = autosomal recessive phenotype, 40 = dosage sensitivity unlikely.

triplosensitivity_scoreINTEGER

Triplosensitivity assessment score. The field is informational for the nuclear SNV/indel classifier and is used as dosage-sensitivity evidence by the dedicated SV/CNV workflow.

Structural variants and CNVs

The SV/CNV module evaluates constitutional deletions and duplications under the Riggs 2020 framework and uses ClinGen dosage regions and gene-level sensitivity evidence. See SV/CNV Methodology.

Haploinsufficiency Score Interpretation

Score	Evidence Level	Meaning	Usage in Classification
3	Sufficient evidence	Multiple independent studies demonstrate haploinsufficiency causes disease. Gene is intolerant to loss of one copy.	Used as proxy for autosomal dominant inheritance in BS1 threshold selection.
2	Emerging evidence	Some evidence suggests haploinsufficiency, but additional studies needed.	Informational. Does not affect ACMG criteria thresholds.
1	Little evidence	Limited or conflicting evidence for haploinsufficiency.	Informational. Does not affect ACMG criteria thresholds.
0	No evidence	No published evidence for haploinsufficiency.	Does not affect ACMG criteria.
30	Gene associated with autosomal recessive phenotype	Disease mechanism requires biallelic variants.	AR proxy. Used to calibrate BS1 frequency thresholds and BP2 logic.
40	Dosage sensitivity unlikely	Evidence suggests the gene tolerates copy number changes.	Used in BP2: dosage sensitivity unlikely supports benign interpretation for compound heterozygotes.

Limitations

ClinGen covers approximately 1,600 genes. Variants in unassessed genes will have NULL dosage scores.

Dosage sensitivity is a gene-level property. It does not distinguish between different variant types or positions within the gene.

The haploinsufficiency score is used as an inheritance proxy, not a direct measure of variant pathogenicity.

Genes with score 0 (no evidence) are not the same as genes with negative evidence -- absence of evidence is not evidence of absence.

Reference

Rehm HL, et al. "ClinGen -- The Clinical Genome Resource." New England Journal of Medicine. 2015;372(23):2235-2242. PMID: 26014595.