KCNB2

Chr 8

potassium voltage-gated channel subfamily B member 2

Also known as: KV2.2

NCBI Gene: 9312 ENSG00000182674 UniProt: Q92953

The KCNB2 protein forms voltage-gated potassium channels that regulate neuronal excitability and transmembrane potassium transport, functioning as delayed-rectifier channels primarily in brain and smooth muscle cells. Mutations cause autosomal dominant epileptic encephalopathy with developmental delay and intellectual disability, typically presenting in early childhood. This gene is highly constrained against loss-of-function mutations, indicating that KCNB2 variants are likely to have significant clinical impact.

ResearchSummary from RefSeq, UniProt

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. The gene is expressed in gastrointestinal smooth muscle cells. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.26

Clinical Summary— KCNB2

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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

2 unique Pathogenic / Likely Pathogenic· 89 VUS of 113 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.996

Z-score 4.53

OE 0.10 (0.04–0.26)

Highly constrained

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

Missense Constraint?

2.25Z-score

OE missense 0.72 (0.66–0.79)

368 obs / 511.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.26)

0≤0.351.4

Missense OE?0.72 (0.66–0.79)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 3 / 29.6Missense obs/exp: 368 / 511.2Syn Z: -1.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKCNB2-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.5576th %ile

GOF

0.75top 25%

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-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 loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.26

GOFprediction above median

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.

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

ClinVar Variant Classifications

113 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS89

Likely Benign13

Benign8

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	0	89	0	0	89
Likely Benign	0	8	0	5	13
Benign	0	1	2	5	8
Conflicting	—				1
Total	0	100	2	10	113

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap KCNB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →