KCNB1

Chr 20AD

potassium voltage-gated channel subfamily B member 1

Also known as: DEE26, DRK1, Kv2.1

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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

116 unique Pathogenic / Likely Pathogenic· 317 VUS of 874 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 →

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GeneReview available — KCNB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.00 (0.00–0.13)

0≤0.351.4

Missense OE?0.47 (0.42–0.52)

0≤0.61.4

Synonymous OE?0.91

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

This gene — mechanism propensity

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 · 22% of P/LP variants are LoF · LOEUF 0.13

GOFprediction above median · 1 literature citation · 78% 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.1

GOFA KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures.2

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

References

ClinVar Variant Classifications

874 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45

Likely Pathogenic71

VUS317

Likely Benign312

Benign67

Conflicting59

Pathogenic

Likely Pathogenic

317

VUS

312

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	31	0	0	45
Likely Pathogenic	11	60	0	0	71
VUS	27	280	9	1	317
Likely Benign	3	67	20	222	312
Benign	1	56	1	9	67
Conflicting	—				59
Total	56	494	30	232	871

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap KCNB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →