KCNB1

Chr 20AD

potassium voltage-gated channel subfamily B member 1

NCBI Gene: 3745 ENSG00000158445 UniProt: Q14721 OMIM: 600397

This gene encodes a delayed rectifier voltage-gated potassium channel that regulates neuronal excitability and is highly constrained against loss-of-function variants. Mutations cause developmental and epileptic encephalopathy 26 through an autosomal dominant inheritance pattern, predominantly through loss-of-function mechanisms leading to haploinsufficiency.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.131 OMIM phenotype

Clinical Summary— KCNB1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 124 VUS of 300 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.13LOEUF

pLI 1.000

Z-score 4.54

OE 0.00 (0.00–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

4.27Z-score

OE missense 0.47 (0.42–0.52)

241 obs / 513.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.13)

0≤0.351.4

Missense OE0.47 (0.42–0.52)

0≤0.61.4

Synonymous OE0.91

0≤1.21.6

LoF obs/exp: 0 / 24.0Missense obs/exp: 241 / 513.1Syn Z: 1.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNB1-related epileptic encephalopathy, early infantileOTHERAD

0.5870th %ile

GOF

0.7126th %ile

LOF

0.66top 25%

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

LOFprediction above median · 18% of P/LP variants are LoF · LOEUF 0.13

GOFprediction above median · 1 literature citation · 82% of P/LP are missense

DN1 literature citation

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

DNEpilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant.PMID:33132203

GOFA KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures.PMID:36618935

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