HCN2

Chr 19AD

hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2

ENSG00000099822 UniProt: Q9UL51 OMIM: 602781

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.453 OMIM phenotypes

Clinical Summary— HCN2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.45LOEUF

pLI 0.489

Z-score 3.53

OE 0.21 (0.11–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.41Z-score

OE missense 0.53 (0.47–0.59)

222 obs / 418.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.21 (0.11–0.45)

0≤0.351.4

Missense OE0.53 (0.47–0.59)

0≤0.61.4

Synonymous OE1.55

0≤1.21.6

LoF obs/exp: 5 / 23.5Missense obs/exp: 222 / 418.4Syn Z: -5.75

0.6841th %ile

GOF

0.83top 10%

LOF

0.48top 25%

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.

GOFprediction above median · 1 literature citation

DNprediction above median

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

GOFGain-of-function HCN2 variants in genetic epilepsyPMID:29064616

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.