KCNK4

protein-coding

potassium two pore domain channel subfamily K member 4, the group of Potassium two pore domain channel subfamily K

Gene summary

This gene encodes a member of the TWIK-related arachidonic acid-stimulated two pore potassium channel subfamily. The encoded protein homodimerizes and functions as an outwardly rectifying channel. This channel is regulated by polyunsaturated fatty acids, temperature and mechanical deformation of the lipid membrane. This protein is expressed primarily in neural tissues and may be involved in regulating the noxious input threshold in dorsal root ganglia neurons. Alternate splicing results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream testis expressed 40 (TEX40) gene, as represented in GeneID: 106780802. [provided by RefSeq, Nov 2015]

MANE transcript

NM_033310.3

Inheritance

ClinVar variants

P:9U:215B:212

Top phenotype

Facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth syndrome

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr11:64,291,302-64,300,031

External References & Databases

Ensembl (ENSG00000182450)

Transcript & Mutation Effects

hg38 • Region Span ~8.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032714

Submitter: Labcorp Genetics (formerly Invitae)

facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032714

Submitter: ClinGen

The *KCNK4* gene is located on chromosome 11 at 11q13.1 and encodes the potassium channel subfamily K, member 4, a 2-pore domain potassium ion channel that is expressed almost exclusively in the nervous system, and controls the resting membrane potential. *KCNK4* was first reported in relation to autosomal dominant facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG) syndrome in 2018 (Bauer et al., PMID: 30290154). FHEIG syndrome is a rare, multiple congenital anomalies syndrome characterized by variable intellectual disability and/or developmental delay, epilepsy, generalized hypertrichosis, and severe gingival overgrowth. Seven unique missense variants have been reported in 12 probands in 6 publications and in ClinVar (PMIDs: 30290154, 32981868, 37931962, 36683851, 37750049, 39146707. ClinVar: SCV002157627.3, SCV002761982.1) and are included in this curation. The mechanism of pathogenicity at this time is unknown. This gene-disease relationship is also supported by expression in relevant tissues and by biochemical function studies (PMIDs: 32913098, 36225112). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date September 4th, 2024 (SOP Version 11).

facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032714

Submitter: PanelApp Australia

facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032714

Submitter: G2P

facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032714

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth syndromeAD

Manifestation: Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 30290154

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNK4 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 450

not specifiedTotal: 82

Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndromeTotal: 18

KCNK4-related disorderTotal: 16

Gingival overgrowthTotal: 2

Abnormal facial shapeTotal: 2

Generalized hypertrichosisTotal: 2

SeizureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033310.3. 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	123 clinvar	3 clinvar	129
missense	1 clinvar	8 clinvar	188 clinvar	73 clinvar	8 clinvar	278
nonsense			8 clinvar	2 clinvar		10
start loss						0
frameshift			13 clinvar	2 clinvar		15
splice donor/acceptor (+/-2bp)			3 clinvar	1 clinvar		4
Total	1	8	215	201	11	436

Highest pathogenic variant AF is 6.840769e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033310.3	RefSeq	NP_201567.1	6	MANE Select
ENST00000422670.7	Ensembl	ENSP00000402797.2	6	MANE Select
NM_001317090.2	RefSeq	NP_001304019.1	6	Standard
ENST00000394525.6	Ensembl	ENSP00000378033.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuronal System
Phase 4 - resting membrane potential
Cardiac conduction
Muscle contraction
TWIK related potassium channel (TREK)

Biological Process

potassium ion transport
memory
sensory perception of pain
stabilization of membrane potential
regulation of ion transmembrane transport

Molecular Function

voltage-gated ion channel activity
potassium channel activity
potassium ion leak channel activity
temperature-gated cation channel activity
mechanosensitived potassium channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
potassium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000539216
Coding exons: 6
Length: 8730
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125745
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.754	197	229	0.860	0.0000121	2440
Missense (PolyPhen)		76	90.557	0.83925		940
Synonymous	-0.807	119	108	1.10	0.00000577	900
Loss of Function	2.03	6	14.3	0.421	7.18e-7	151

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Voltage-insensitive potassium channel (PubMed:22282805). Channel opening is triggered by mechanical forces that deform the membrane (PubMed:22282805, PubMed:25471887, PubMed:25500157). Channel opening is triggered by raising the intracellular pH to basic levels (By similarity). The channel is inactive at 24 degrees Celsius (in vitro); raising the temperature to 37 degrees Celsius increases the frequency of channel opening, with a further increase in channel activity when the temperature is raised to 42 degrees Celsius (By similarity). Plays a role in the perception of pain caused by heat (By similarity). Plays a role in the sensory perception of pain caused by pressure (By similarity). {ECO:0000250|UniProtKB:G3V8V5, ECO:0000250|UniProtKB:O88454, ECO:0000269|PubMed:22282805, ECO:0000269|PubMed:25471887, ECO:0000269|PubMed:25500157}.;

Intolerance Scores

LoFtool: 0.644
RVIS EVS: -0.2
RVIS percentile EVS: 38.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.655

Gene Damage Prediction

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