KCNK4

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

Basic information

Region (hg38): 11:64291302-64300031

Links

ENSG00000182450 ∙ NCBI:50801 ∙ OMIM:605720 ∙ HGNC:6279 ∙ Uniprot:Q9NYG8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (Moderate), mode of inheritance: AD
• facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth syndrome	AD	General	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	Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic	30290154

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNK4 gene.

• not provided (2 variants)
• Abnormal facial shape;Generalized hypertrichosis;Intellectual disability;Gingival overgrowth;Seizure (1 variants)
• Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNK4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	101	5	107
missense	3	3	185	21	9	221
nonsense			6	1		7
start loss						0
frameshift			11			11
inframe indel			6			6
splice donor/acceptor (+/-2bp)						0
splice region			5	13	2	20
non coding			4	15	4	23
Total	3	3	213	138	18

Variants in KCNK4

This is a list of pathogenic ClinVar variants found in the KCNK4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-64293022-C-A			Uncertain significance (Aug 07, 2023)
11-64293023-G-A		not specified	Uncertain significance (Jul 01, 2024)
11-64293029-C-T			Likely benign (Oct 23, 2024)
11-64293031-A-G			Uncertain significance (Dec 17, 2024)
11-64293034-C-G			Likely benign (Oct 23, 2024)
11-64293041-C-T			Likely benign (Oct 23, 2024)
11-64293042-C-T		KCNK4-related disorder	Benign/Likely benign (Feb 03, 2025)
11-64293051-G-A			Likely benign (Jan 01, 2023)
11-64293054-G-T			Likely benign (Sep 25, 2024)
11-64293060-G-A			Likely benign (Dec 03, 2022)
11-64293072-G-A			Likely benign (Aug 23, 2023)
11-64293073-T-C			Uncertain significance (Sep 07, 2022)
11-64293073-T-G			Uncertain significance (May 25, 2022)
11-64293074-C-G			Uncertain significance (Sep 25, 2024)
11-64293081-C-T			Likely benign (Sep 19, 2023)
11-64293091-C-G			Uncertain significance (Aug 18, 2023)
11-64293092-G-A			Uncertain significance (Aug 17, 2021)
11-64293094-G-A			Likely benign (Jan 06, 2025)
11-64293095-C-T			Uncertain significance (Sep 21, 2021)
11-64293098-T-C			Uncertain significance (Oct 14, 2022)
11-64293105-G-A			Likely benign (Oct 22, 2024)
11-64293111-C-A		not specified	Conflicting classifications of pathogenicity (Jan 28, 2025)
11-64293113-A-G			Uncertain significance (Jul 25, 2023)
11-64293121-G-T			Likely benign (Oct 24, 2024)
11-64293122-C-T			Uncertain significance (Jul 28, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNK4	protein_coding	protein_coding	ENST00000539216	6	8730

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00568	0.974	125718	0	27	125745	0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.754	197	229	0.860	0.0000121	2440
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000362	0.000360
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000110	0.000105
Middle Eastern	0.000163	0.000163
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Neuronal System;Phase 4 - resting membrane potential;Cardiac conduction;Muscle contraction;TWIK related potassium channel (TREK);Tandem pore domain potassium channels;Potassium Channels (Consensus)

Intolerance Scores

• loftool: 0.644
• rvis_EVS: -0.2
• rvis_percentile_EVS: 38.82

Haploinsufficiency Scores

• pHI: 0.184
• hipred: N
• hipred_score: 0.482
• ghis: 0.619

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.655

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnk4

Gene ontology

• Biological process: potassium ion transport;memory;sensory perception of pain;stabilization of membrane potential;regulation of ion transmembrane transport;sensory perception of temperature stimulus;detection of mechanical stimulus involved in sensory perception of touch;cellular response to mechanical stimulus;cellular response to fatty acid;cellular response to alkaline pH;cellular response to temperature stimulus;potassium ion transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;potassium channel complex
• Molecular function: voltage-gated ion channel activity;potassium channel activity;potassium ion leak channel activity;temperature-gated cation channel activity;mechanosensitived potassium channel activity