CACNA1B

Chr 9AR

calcium voltage-gated channel subunit alpha1 B

ENSG00000148408 UniProt: Q00975 OMIM: 601012

The CACNA1B protein forms the alpha-1B subunit of N-type voltage-gated calcium channels, which mediate calcium entry into excitable cells and control neurotransmitter release at synapses, pain signaling, and neuronal migration. Autosomal recessive mutations cause a neurodevelopmental disorder characterized by seizures and nonepileptic hyperkinetic movements. The protein is highly intolerant to loss-of-function mutations, suggesting pathogenicity occurs through severe disruption of calcium channel function.

OMIM ResearchSummary from OMIM, UniProt

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This alpha-1B subunit gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group. They are involved in pain signaling (PubMed:25296916). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons. Mediates Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity)

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— CACNA1B

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder with motor features · ARModerate

Moderate evidence — consider for supplementary testing

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 1.000

Z-score 7.85

OE 0.16 (0.11–0.24)

Highly constrained

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

Missense Constraint?

4.52Z-score

OE missense 0.65 (0.61–0.69)

841 obs / 1299.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.16 (0.11–0.24)

0≤0.351.4

Missense OE?0.65 (0.61–0.69)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 16 / 101.2Missense obs/exp: 841 / 1299.1Syn Z: -0.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCACNA1B-related neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movementsLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5967th %ile

GOF

0.74top 25%

LOF

0.56top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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