KCNK9

Chr 8AD

potassium two pore domain channel subfamily K member 9

NCBI Gene: 51305 ENSG00000169427 UniProt: Q9NPC2 OMIM: 605874

The protein functions as a pH-dependent potassium channel that regulates neuronal excitability by conducting voltage-dependent outward currents and controlling action potential firing in various brain regions including cerebellum and hippocampus. Mutations cause Birk-Barel syndrome, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants and shows imprinted expression in the brain with preferential maternal allele expression.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

DNmechanismADLOEUF 0.311 OMIM phenotype

Clinical Summary— KCNK9

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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GeneReview available — KCNK9

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.31LOEUF

pLI 0.955

Z-score 2.89

OE 0.00 (0.00–0.31)

Highly constrained

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

Missense Constraint

2.90Z-score

OE missense 0.48 (0.41–0.56)

118 obs / 246.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.31)

0≤0.351.4

Missense OE0.48 (0.41–0.56)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 0 / 9.7Missense obs/exp: 118 / 246.2Syn Z: -0.84

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKCNK9-related Birk-Barel syndromeDNAD

0.6841th %ile

GOF

0.83top 10%

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOFLOEUF 0.31

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFurthermore, expression of dominant-negative mutant KCNK9, responsible for the disease, and electrophysiological experiments demonstrated that ion channel function was involved in the migration defect. Calcium imaging revealed that KCNK9 knockdown or expression of dominant-negative mutant KCNK9 incrPMID:23236211

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.