HCN3

protein-coding

hyperpolarization activated cyclic nucleotide gated potassium channel 3, the group of Cyclic nucleotide gated channels

Gene summary

This gene encodes a multi-pass membrane protein that functions as a voltage gated cation channel. The encoded protein is a member of a family of closely related cyclic adenosine monophosphate-binding channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

MANE transcript

NM_020897.3

Inheritance

—

ClinVar variants

U:115B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr1:155,277,463-155,289,848

External References & Databases

Ensembl (ENSG00000143630)

Transcript & Mutation Effects

hg38 • Region Span ~12.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HCN3 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 109

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020897.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar			1
missense			114 clinvar	3 clinvar		117
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	115	3	0	118

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020897.3	RefSeq	NP_065948.1	8	MANE Select
ENST00000368358.4	Ensembl	ENSP00000357342.3	8	MANE Select
ENST00000877986.1	Ensembl	ENSP00000548045.1	7	Standard
ENST00000877986.2	Ensembl	ENSP00000548045.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuronal System
HCN channels
Potassium Channels

Biological Process

regulation of ion transmembrane transport
sodium ion transmembrane transport
regulation of membrane potential
cellular response to cAMP
potassium ion transmembrane transport

Molecular Function

voltage-gated sodium channel activity
voltage-gated potassium channel activity
protein binding
cAMP binding

Cellular Component

plasma membrane
integral component of plasma membrane
dendrite
neuronal cell body
cone cell pedicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368358
Coding exons: 8
Length: 12266
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.52	424	522	0.813	0.0000353	4917
Missense (PolyPhen)		92	111.29	0.82666		1068
Synonymous	1.13	190	211	0.901	0.0000129	1748
Loss of Function	2.57	12	26.2	0.458	0.00000138	273

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000062	0.000046	rare
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hyperpolarization-activated potassium channel. May also facilitate the permeation of sodium ions. {ECO:0000269|PubMed:16043489}.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.101
RVIS EVS: 0.07
RVIS percentile EVS: 59.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium