KCNK3

protein-coding

potassium two pore domain channel subfamily K member 3, the group of Potassium two pore domain channel subfamily K

Gene summary

This gene encodes a member of the superfamily of potassium channel proteins that contain two pore-forming P domains. The encoded protein is an outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane. Although three transcripts are detected in northern blots, there is currently no sequence available to confirm transcript variants for this gene. [provided by RefSeq, Aug 2008]

MANE transcript

NM_002246.3

Inheritance

ClinVar variants

P:10U:167B:97

Top phenotype

Pulmonary hypertension, primary, 4

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr2:26,692,722-26,733,420

External References & Databases

Ensembl (ENSG00000171303)

Transcript & Mutation Effects

hg38 • Region Span ~40.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pulmonary hypertension, primary, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014136

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

pulmonary arterial hypertensionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

KCNK3 (also known as TASK1) was first reported as a risk factor for autosomal dominant pulmonary arterial hypertension in 2013 by Ma et al. (PMID: 23883380). Using variant filtering of whole-exome sequence data from three members of a multi-generational family, a novel heterozygous missense variant was identified that co-segregated with the disease, but with some evidence of reduced penetrance. Independent validation by sequence analysis detected additional missense variants in 2/92 familial and 3/230 sporadic cases. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of genetic evidence: 7 points. Variants in this gene have since been reported in at least 22 probands in 11 publications. All variants are rare, likely deleterious missense variants. Ma et al. and Cunningham et al. (PMIDs: 23883380; 30365877) have demonstrated a functional impact for 8 variants. Summary of experimental evidence: 5 points. The gene-disease association is supported by expression studies, functional alteration and an animal model of disease (PMIDs: 16574908; 26912814; 31347976). The evidence supporting this gene-disease relationship has been replicated over 8 years. In summary, KCNK3 is definitively associated with autosomal dominant pulmonary arterial hypertension. This classification was approved by the ClinGen PH Working Group on Feb 10, 2021.

KCNK3-related developmental delay with sleep apneaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700360

Submitter: G2P

heritable pulmonary arterial hypertensionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017148

Submitter: Orphanet

Clinical Genomic Database (CGD)

Pulmonary hypertension, primary, 4AD

Manifestation: Cardiovascular; Pulmonary

Intervention: Cardiovascular; Pulmonary

Rationale: While prognosis is overall poor, medical therapy may be beneficial, though heart/lung transplantation may be required; Control of complications may be beneficial

Refs: 23883380

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNK3 variants in ClinVar

8 Conditions Cataloged

Pulmonary hypertension, primary, 4Total: 226

Inborn genetic diseasesTotal: 48

not providedTotal: 37

not specifiedTotal: 10

KCNK3-related disorderTotal: 7

Pulmonary arterial hypertensionTotal: 2

Autism spectrum disorderTotal: 2

Pulmonary hypertension, primary, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002246.3. 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	86 clinvar	2 clinvar	91
missense	6 clinvar	4 clinvar	160 clinvar	9 clinvar		179
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	6	4	167	95	2	274

Highest pathogenic variant AF is 0.000013140432

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002246.3	RefSeq	NP_002237.1	2	MANE Select
ENST00000302909.4	Ensembl	ENSP00000306275.3	2	MANE Select
ENST00001125328.1	Ensembl	ENSP00000795133.1	2	Standard
XM_005264293.3	RefSeq	XP_005264350.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cortisol synthesis and secretion - Homo sapiens (human)
Aldosterone synthesis and secretion - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
Antiarrhythmic Pathway, Pharmacodynamics

Biological Process

potassium ion transport
chemical synaptic transmission
brain development
stabilization of membrane potential
ion transmembrane transport

Molecular Function

ion channel activity
open rectifier potassium channel activity
potassium channel activity
protein C-terminus binding
potassium ion leak channel activity

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302909
Coding exons: 2
Length: 40670
Individuals with no LoFs: 123670
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 123672
p: 0.00000809

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.55	103	266	0.387	0.0000190	2467
Missense (PolyPhen)		13	105.16	0.12362		1002
Synonymous	3.49	84	136	0.619	0.0000113	819
Loss of Function	2.92	1	11.8	0.0844	5.78e-7	121

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000059	0.000055	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000097	0.0000091	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward. {ECO:0000269|PubMed:23169818, ECO:0000269|PubMed:9312005}.;

Recessive Scores

pRec: 0.230

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.909

Gene Damage Prediction

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