KCNJ3

Chr 2

potassium inwardly rectifying channel subfamily J member 3

Also known as: GIRK1, KGA, KIR3.1

NCBI Gene: 3760 ENSG00000162989 UniProt: P48549

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]

Research

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.26

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.991

Z-score 3.78

OE 0.05 (0.02–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.06Z-score

OE missense 0.33 (0.28–0.39)

97 obs / 292.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.26)

0≤0.351.4

Missense OE?0.33 (0.28–0.39)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 1 / 18.6Missense obs/exp: 97 / 292.6Syn Z: 1.10

Background carrier burden — how many people carry a rare variant somewhere in KCNJ3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 530

302 rare PASS variants

Rare truncating (LoF)

1 in 21,000

11 rare PASS variants

Rare synonymous (reference)

1 in 410

246 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCNJ3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 620	1 in 46,000
South Asian	~43k	1 in 560	1 in 2,300
Remaining (unassigned)	~30k	1 in 600	≈ 1 in 30,000
European (Finnish)	~27k	1 in 580	≈ 1 in 12,000
Admixed American	~22k	1 in 460	none seen
African / African American	~21k	1 in 620	≈ 1 in 21,000
East Asian	~20k	1 in 470	none seen
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	1 in 260	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓