KCNAB2

Chr 1

potassium voltage-gated channel subfamily A regulatory beta subunit 2

Also known as: AKR6A5, HKvbeta2, HKvbeta2.1, HKvbeta2.2, KCNA2B, KV-BETA-2

NCBI Gene: 8514 ENSG00000069424 UniProt: Q13303 OMIM: 601142

KCNAB2 encodes a regulatory beta subunit of voltage-gated potassium channels that promotes channel inactivation and prevents neuronal hyperexcitability, with additional aldoketoreductase enzymatic activity. Mutations cause autosomal dominant epileptic encephalopathy with onset typically in infancy or early childhood. The gene is highly constrained against loss-of-function variants (pLI = 0.80, LOEUF = 0.385), indicating strong selective pressure for proper gene function.

OMIM 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, shaker-related subfamily. This member is one of the beta subunits, which are auxiliary proteins associating with functional Kv-alpha subunits. This member alters functional properties of the KCNA4 gene product. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.39

Clinical Summary— KCNAB2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.800

Z-score 3.96

OE 0.18 (0.10–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.60Z-score

OE missense 0.55 (0.48–0.63)

145 obs / 263.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.18 (0.10–0.39)

0≤0.351.4

Missense OE?0.55 (0.48–0.63)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 27.3Missense obs/exp: 145 / 263.6Syn Z: 0.44

This gene — mechanism propensity

0.6648th %ile

GOF

0.4973th %ile

LOF

0.50top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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.