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ClinGen
The Clinical Genome Resource (ClinGen) provides expert-curated dosage sensitivity assessments for genes. Haploinsufficiency and triplosensitivity scores indicate whether a gene is sensitive to copy number changes, which serves as a proxy for inheritance pattern in ACMG classification.
Database Details
Role in ACMG Classification
ClinGen dosage scores provide inheritance pattern proxies that calibrate frequency-based ACMG criteria:
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%).
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 assessment score. Values 0-3 indicate evidence level for haploinsufficiency. Special values: 30 = autosomal recessive phenotype, 40 = dosage sensitivity unlikely.
Triplosensitivity assessment score. Same 0-3 scale as haploinsufficiency. Indicates sensitivity to gene duplication (three copies). Currently informational in Helix Insight and not directly used in ACMG criteria.
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.