KCNJ10

Chr 1AR

potassium inwardly rectifying channel subfamily J member 10

Also known as: BIRK-10, KCNJ13-PEN, KIR1.2, KIR4.1, SESAME

NCBI Gene: 3766 ENSG00000177807 UniProt: P78508 OMIM: 602208

The protein functions as an inwardly rectifying potassium channel that contributes to potassium buffering by glial cells in the brain. Biallelic mutations cause SESAME syndrome (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) and can contribute to enlarged vestibular aqueduct in a digenic pattern, both inherited in an autosomal recessive manner. The pathogenic mechanism appears to involve loss of normal channel function, disrupting potassium homeostasis in neural and other tissues.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Enlarged vestibular aqueduct, digenicMIM #600791

SESAME syndromeMIM #612780

UniProtSeizures, sensorineural deafness, ataxia, impaired intellectual development, and electrolyte imbalance

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · EAST syndrome · AR · ClinGen 2023
Strong · paroxysmal dyskinesia · AD · PanelApp Australia
Supportive · Pendred syndrome · AR · Orphanet
Disputed · enlarged vestibular aqueduct syndrome · AD · ClinGen 2018 — evidence questions this relationship

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.76

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.76LOEUF

pLI 0.150

Z-score 2.09

OE 0.29 (0.13–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.48Z-score

OE missense 0.72 (0.63–0.82)

161 obs / 223.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.13–0.76)

0≤0.351.4

Missense OE?0.72 (0.63–0.82)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 3 / 10.2Missense obs/exp: 161 / 223.0Syn Z: -0.15

Background carrier burden — how many people carry a rare variant somewhere in KCNJ10?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 98

401 rare PASS variants

Rare truncating (LoF)

1 in 4,100

41 rare PASS variants

Rare synonymous (reference)

1 in 360

202 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCNJ10. 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 100	1 in 3,800
South Asian	~43k	1 in 140	1 in 1,900
Remaining (unassigned)	~30k	1 in 89	1 in 5,300
European (Finnish)	~27k	1 in 330	≈ 1 in 27,000
Admixed American	~22k	1 in 97	1 in 3,700
African / African American	~21k	1 in 160	1 in 1,400
East Asian	~20k	1 in 180	1 in 2,500
Ashkenazi Jewish	~13k	1 in 540	none seen
Middle Eastern	~2,884	1 in 140	≈ 1 in 650

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 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓