HCN2

Chr 19AD

hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2

Also known as: BCNG-2, BCNG2, EIG17, FEB2, GEFSP11, HAC-1

NCBI Gene: 610 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

The protein encoded by this gene is a hyperpolarization-activated cation channel involved in the generation of native pacemaker activity in the heart and in the brain. The encoded protein is activated by cAMP and can produce a fast, large current. Defects in this gene were noted as a possible cause of some forms of epilepsy. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 258 VUS of 373 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.21 (0.11–0.45)

0≤0.351.4

Missense OE?0.53 (0.47–0.59)

0≤0.61.4

Synonymous OE?1.55

0≤1.21.6

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

This gene — mechanism propensity

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 · 92% of P/LP are missense

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 epilepsy1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29064616 ↗

ClinVar Variant Classifications

373 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic3

VUS258

Likely Benign58

Benign24

Conflicting10

Pathogenic

Likely Pathogenic

258

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	8	0	0	9
Likely Pathogenic	0	3	0	0	3
VUS	10	243	5	0	258
Likely Benign	1	26	4	27	58
Benign	0	1	9	14	24
Conflicting	—				10
Total	12	281	18	41	362

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

26 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap HCN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →