CACNB2

Chr 10AD

calcium voltage-gated channel auxiliary subunit beta 2

Also known as: CAB2, CACNLB2, CAVB2, MYSB

NCBI Gene: 783 ENSG00000165995 UniProt: Q08289 OMIM: 600003

This gene encodes a beta subunit of voltage-dependent calcium channels that increases peak calcium current and modulates channel activation and inactivation, particularly contributing to beta-adrenergic regulation of heart rate and contractile force in cardiomyocytes. Mutations cause Brugada syndrome 4, a cardiac arrhythmia disorder with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI nearly 1.0), indicating that complete loss of function is likely incompatible with survival.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.691 OMIM phenotype

Clinical Summary— CACNB2

🧬

Gene-Disease Validity (ClinGen)

cardiogenetic disease · ADDisputed

Disputed — evidence questions this relationship

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 541 VUS of 1140 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — CACNB2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 2.95

OE 0.45 (0.30–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.07Z-score

OE missense 0.99 (0.91–1.08)

390 obs / 393.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.30–0.69)

0≤0.351.4

Missense OE?0.99 (0.91–1.08)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 15 / 33.4Missense obs/exp: 390 / 393.7Syn Z: -2.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCACNB2-related hypertrophic cardiomyopathyOTHERAD

limitedCACNB2-related short QT syndromeOTHERAD

limitedCACNB2-related Brugada syndromeOTHERAD

This gene — mechanism propensity

0.7230th %ile

GOF

0.5955th %ile

LOF

0.51top 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.

ClinVar Variant Classifications

1140 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS541

Likely Benign435

Benign100

Conflicting46

Pathogenic

Likely Pathogenic

541

VUS

435

Likely Benign

100

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	1	0	0	0	1
VUS	24	481	31	5	541
Likely Benign	2	16	183	234	435
Benign	0	2	94	4	100
Conflicting	—				46
Total	27	500	308	243	1,124

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap CACNB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →