CACNB3

Chr 12

calcium voltage-gated channel auxiliary subunit beta 3

Also known as: CAB3, CACNLB3

NCBI Gene: 784 ENSG00000167535 UniProt: P54284 OMIM: 601958

This protein is a regulatory beta subunit of voltage-gated calcium channels that increases peak calcium currents and modulates channel activation and inactivation properties. Mutations cause autosomal recessive juvenile myoclonic epilepsy with onset in adolescence. The gene is highly constrained against loss-of-function variants (LOEUF 0.644), suggesting intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a regulatory beta subunit of the voltage-dependent calcium channel. Beta subunits are composed of five domains, which contribute to the regulation of surface expression and gating of calcium channels and may also play a role in the regulation of transcription factors and calcium transport. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.64

Clinical Summary— CACNB3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

67 VUS of 79 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.000

Z-score 3.01

OE 0.39 (0.24–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.17Z-score

OE missense 0.65 (0.58–0.73)

204 obs / 311.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.39 (0.24–0.64)

0≤0.351.4

Missense OE?0.65 (0.58–0.73)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 11 / 28.3Missense obs/exp: 204 / 311.8Syn Z: 0.60

This gene — mechanism propensity

0.7131th %ile

GOF

0.6344th %ile

LOF

0.3939th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

79 submitted variants in ClinVar

ClinVar

Classification Summary

VUS67

Benign1

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	67	0	67
Likely Benign	0	0	0
Benign	0	1	1
Total	67	1	68

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap CACNB3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →