KCNH4

protein-coding

potassium voltage-gated channel subfamily H member 4, the group of PAS domain containing|Potassium voltage-gated channels

Gene summary

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. The gene is brain-specific, and located in the neocortex and the striatum. It may be involved in cellular excitability of restricted neurons in the central nervous system. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012285.3

Inheritance

—

ClinVar variants

U:126B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr17:42,156,891-42,181,142

External References & Databases

Ensembl (ENSG00000089558)

Transcript & Mutation Effects

hg38 • Region Span ~24.3 kb

Loading mutation effect viewer...

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 KCNH4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 123

not providedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012285.3. 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				3 clinvar	1 clinvar	4
missense			123 clinvar	3 clinvar		126
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	126	6	1	133

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012285.3	RefSeq	NP_036417.1	16	MANE Select
ENST00000264661.4	Ensembl	ENSP00000264661.2	16	MANE Select
ENST00000607371.5	Ensembl	ENSP00000475564.1	16	Standard
ENST00000607371.6	Ensembl	ENSP00000475564.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kcnh4a	Danio rerio	Structure: circadian sleep/wake cycle, sleep Quality: decreased duration abnormal

Gene / Model

Organism

Observed Phenotype

kcnh4a

Danio rerio

Structure: circadian sleep/wake cycle, sleep

Quality: decreased duration

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuronal System
Voltage gated Potassium channels
Potassium Channels

Biological Process

potassium ion transport
regulation of ion transmembrane transport
regulation of membrane potential
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
voltage-gated potassium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264661
Coding exons: 16
Length: 24388
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.94	435	645	0.674	0.0000423	6482
Missense (PolyPhen)		86	190	0.45263		2081
Synonymous	0.565	268	280	0.957	0.0000186	2239
Loss of Function	5.48	4	42.6	0.0940	0.00000229	450

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000068	0.000062	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits an outward current, but shows no inactivation. Channel properties may be modulated by cAMP and subunit assembly.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.00241
RVIS EVS: -1.68
RVIS percentile EVS: 2.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.685

Gene Damage Prediction

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