HCN1

Chr 5AD

hyperpolarization activated cyclic nucleotide gated potassium channel 1

Also known as: BCNG-1, BCNG1, DEE24, EIEE24, GEFSP10, HAC-2

NCBI Gene: 348980 ENSG00000164588 UniProt: O60741 OMIM: 602780

This gene encodes a hyperpolarization-activated cation channel that contributes to pacemaker currents in neurons and can form homo- or heterodimeric potassium channels. Mutations cause developmental and epileptic encephalopathy 24 and generalized epilepsy with febrile seizures plus type 10 through an autosomal dominant inheritance pattern. The pathogenic mechanism appears to predominantly involve loss-of-function, consistent with the gene's high intolerance to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 24MIM #615871

Generalized epilepsy with febrile seizures plus, type 10MIM #618482

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · generalized epilepsy with febrile seizures plus · AD · ClinGen 2023
Definitive · developmental and epileptic encephalopathy, 24 · AD · Ambry Genetics
Strong · generalized epilepsy with febrile seizures plus, type 10 · AD · Labcorp Genetics (formerly Invitae)
Supportive · undetermined early-onset epileptic encephalopathy · AD · Orphanet

Interpreting a novel variant

Gain of function is the established mechanism, so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

GOF

Mechanism· annotated

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 5.15

OE 0.06 (0.02–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.66Z-score

OE missense 0.53 (0.48–0.59)

261 obs / 489.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.18)

0≤0.351.4

Missense OE?0.53 (0.48–0.59)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 2 / 34.8Missense obs/exp: 261 / 489.1Syn Z: -2.32

Background carrier burden — how many people carry a rare variant somewhere in HCN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

887 rare PASS variants

Rare truncating (LoF)

1 in 5,000

57 rare PASS variants

Rare synonymous (reference)

1 in 110

604 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HCN1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 7,600
South Asian	~43k	1 in 100	1 in 1,500
Remaining (unassigned)	~30k	1 in 150	1 in 3,700
European (Finnish)	~27k	1 in 330	1 in 2,000
Admixed American	~22k	1 in 100	1 in 1,300
African / African American	~21k	1 in 77	≈ 1 in 5,100
East Asian	~20k	1 in 110	≈ 1 in 4,900
Ashkenazi Jewish	~13k	1 in 280	none seen
Middle Eastern	~2,884	1 in 160	≈ 1 in 1,700

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 8.? see exons ↓