HCN2
Chr 19ADhyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2
Also known as: BCNG-2, BCNG2, EIG17, FEB2, GEFSP11, HAC-1
The protein is a hyperpolarization-activated cation channel that generates pacemaker currents in the heart and brain by conducting sodium and potassium ions. Mutations cause autosomal dominant epilepsy syndromes including generalized epilepsy with febrile seizures plus, familial febrile seizures, and idiopathic generalized epilepsy. Disease can result from multiple mechanisms depending on the specific variant, with some mutations potentially causing gain-of-function effects that alter normal channel properties.
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
3 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
394 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 1 | 10 | 21 | 0 | 32 |
Likely Pathogenic | 0 | 1 | 5 | 0 | 6 |
VUS | 8 | 233 | 15 | 0 | 256 |
Likely Benign | 0 | 19 | 13 | 24 | 56 |
Benign | 0 | 1 | 9 | 15 | 25 |
Conflicting | — | 7 | |||
| Total | 9 | 264 | 63 | 39 | 382 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
HCN2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools