KCNJ3

protein-coding

potassium inwardly rectifying channel subfamily J member 3, the group of Potassium inwardly rectifying channel subfamily J

Gene summary

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and plays an important role in regulating heartbeat. It associates with three other G-protein-activated potassium channels to form a heteromultimeric pore-forming complex that also couples to neurotransmitter receptors in the brain and whereby channel activation can inhibit action potential firing by hyperpolarizing the plasma membrane. These multimeric G-protein-gated inwardly-rectifying potassium (GIRK) channels may play a role in the pathophysiology of epilepsy, addiction, Down's syndrome, ataxia, and Parkinson's disease. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, May 2012]

MANE transcript

NM_002239.4

Inheritance

AD, AR

ClinVar variants

U:28B:2

Top phenotype

Leber congenital amaurosis 16

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr2:154,697,855-154,858,354

External References & Databases

Ensembl (ENSG00000162989)

Transcript & Mutation Effects

hg38 • Region Span ~160.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Leber congenital amaurosis 16AR

Manifestation: 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: 21763485; 25475713; 25921210

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNJ3 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 27

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002239.4. 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				2 clinvar		2
missense			28 clinvar			28
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	28	2	0	30

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002239.4	RefSeq	NP_002230.1	3	MANE Select
ENST00000295101.3	Ensembl	ENSP00000295101.2	3	MANE Select
NM_001260508.2	RefSeq	NP_001247437.1	2	Standard
NM_001260509.2	RefSeq	NP_001247438.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
Serotonergic synapse - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Glutamatergic synapse - Homo sapiens (human)

Biological Process

potassium ion transport
regulation of ion transmembrane transport
response to electrical stimulus
regulation of heart rate by cardiac conduction
membrane repolarization during atrial cardiac muscle cell action potential

Molecular Function

inward rectifier potassium channel activity
protein binding
G-protein activated inward rectifier potassium channel activity
voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization
voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization

Cellular Component

plasma membrane
voltage-gated potassium channel complex
external side of plasma membrane
T-tubule
parallel fiber to Purkinje cell synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295101
Coding exons: 3
Length: 160053
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125711
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.06	97	293	0.332	0.0000166	3301
Missense (PolyPhen)		29	145.45	0.19938		1563
Synonymous	1.10	100	115	0.869	0.00000715	991
Loss of Function	3.78	1	18.6	0.0539	0.00000110	190

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	0.0	absent
Finnish	0.000067	0.000046	rare
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This receptor plays a crucial role in regulating the heartbeat.;

Recessive Scores

pRec: 0.186

Intolerance Scores

RVIS EVS: 0.01
RVIS percentile EVS: 54.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.455

Gene Damage Prediction

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