CACNB2

protein-coding

calcium voltage-gated channel auxiliary subunit beta 2, the group of Calcium voltage-gated channel auxiliary beta subunits|Membrane associated guanylate kinases

Gene summary

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]

Previous symbols:

MYSB
CACNLB2

MANE transcript

NM_201596.3

Inheritance

ClinVar variants

P:2U:495B:300

Top phenotype

Brugada syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr10:18,140,424-18,543,557

External References & Databases

Ensembl (ENSG00000165995)

Transcript & Mutation Effects

hg38 • Region Span ~403.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

short QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: G2P

Brugada syndrome 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012743

Submitter: Genomics England PanelApp

familial hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Brugada syndrome 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012743

Submitter: Labcorp Genetics (formerly Invitae)

cardiogenetic diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100547

Submitter: ClinGen

*CACNB2* was first reported in relation to autosomal dominant cardiogenetic disease in 2007 (Antzelevitch et al., PMID: 17224476). *CACNB2* encodes the β subunit of the L-type voltage gated calcium channel. It regulates trafficking and gating properties of the channel (PMID: 17224476). *CACNB2* has been reported in relation to Brugada syndrome with supporting functional evidence, segregation data, and low gnomAD frequencies (PMIDs: 17224476, 19358333; ClinVar: SCV003918905.2); however there has been a lack of new evidence to emerge since these cases were published. *CACNB2* has only been reported in relation to hypertrophic cardiomyopathy where it was asserted as a possible disease modifier in one Chinese family with a known pathogenic *MYBPC3* variant (Zhang et al., PMID: 28614222). Note that this variant is common in the East Asian population (MAF= 0.01) and may be benign. The relationship of *CACNB2* with short QT syndrome is based on a single report which used a candidate-gene approach in patients with Brugada syndrome and a short QT interval (PMID: 17224476). Because the proband identified as carrying the rare genetic variant (ClinVar Variation ID# 9547) had a positive ajmaline test, his phenotype was regarded by the Short QT Syndrome GCEP to be concordant with Brugada syndrome and not SQTS. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability between the cardiogenetic disease assertions. Therefore, the following disease entities have been lumped into one disease entity: Brugada syndrome 4 (OMIM:611876), hypertrophic cardiomyopathy (PMID: 28614222), and short QT syndrome (PMID: 17224476). We did find differences in the molecular mechanism, inheritance pattern, and phenotypic variability for the reports of *CACNB2* in relation to autism, therefore the split curation for autism will be curated separately. Three missense variants that have been reported in three probands in two publications (PMIDs: 17224476, 19358333) and one ClinVar entry (SCV003918905.2) are included in this curation. Many other *CACNB2* variants have been reported in relation to cardiogenetic disease, but were not scored in this curation due to their allele frequency being above the cutoff established by the HCVD GCEP (>0.00005) or the presence of another variant (PMIDs: 20817017, 22840528, 22090166, 23414114, 26230511, 32824506, 27711072, 35955449, 31737537, 27662471, 28614222). The mechanism of pathogenicity is reported to be loss of function (PMID: 17224476). This gene-disease relationship is also supported by expression studies in heart tissue (PMIDs: 24309898, 21357697, 34307509) and model organisms indicate it may play a role in hypertrophic pathways (PMIDs: 34307509, 17556655, 21357697, 16946137). In summary, the evidence supporting the relationship between *CACNB2* and autosomal dominant cardiogenetic disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *CACNB2* plays in cardiogenetic disease. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on the meeting date June 24, 2025 (SOP Version 11).

Brugada syndrome 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012743

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Brugada syndrome 4NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0012743

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Brugada syndrome 4AD

Manifestation: Cardiovascular

Intervention: Cardiovascular; Pharmacogenomic

Rationale: Surveillance with approximately yearly EKG and medical interventions, including daily quinidine for prevention (though treatment of asymptomatic individuals is controversial), ICD placement in individuals with previous cardiac arrest/syncope, and isoproterenol for electrical storms, may be beneficial; Certain agents should be avoided, including medications such as certain anesthetics, antidepressants, and antipsychotics, and care should be taken in the instance of high fever

Refs: 17224476; 20301690; 22090166

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNB2 variants in ClinVar

19 Conditions Cataloged

Brugada syndrome 4Total: 661

Cardiovascular phenotypeTotal: 540

not providedTotal: 202

not specifiedTotal: 157

CACNB2-related disorderTotal: 132

Brugada syndromeTotal: 11

Hypertrophic cardiomyopathyTotal: 6

CardiomyopathyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_201596.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	238 clinvar	2 clinvar	245
missense		2 clinvar	465 clinvar	52 clinvar	3 clinvar	522
nonsense			5 clinvar	1 clinvar		6
start loss			2 clinvar			2
frameshift			13 clinvar	1 clinvar		14
splice donor/acceptor (+/-2bp)			5 clinvar	3 clinvar		8
Total	0	2	495	295	5	797

Highest pathogenic variant AF is 0.000011632028

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_201596.3	RefSeq	NP_963890.2	14	MANE Select
ENST00000324631.13	Ensembl	ENSP00000320025.8	14	MANE Select
NM_000724.4	RefSeq	NP_000715.2	13	Standard
NM_001167945.2	RefSeq	NP_001161417.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cacnb2a	Danio rerio	Structure: heart tube Quality: increased fragility abnormal

Gene / Model

Organism

Observed Phenotype

cacnb2a

Danio rerio

Structure: heart tube

Quality: increased fragility

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
Cardiac muscle contraction - Homo sapiens (human)
Dilated cardiomyopathy (DCM) - Homo sapiens (human)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)

Biological Process

chemical synaptic transmission
neuromuscular junction development
visual perception
positive regulation of calcium ion transport
calcium ion import

Molecular Function

voltage-gated calcium channel activity
calcium channel activity
protein binding
high voltage-gated calcium channel activity
actin filament binding

Cellular Component

plasma membrane
integral component of plasma membrane
voltage-gated calcium channel complex
photoreceptor ribbon synapse
presynapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324631
Coding exons: 14
Length: 401193
Individuals with no LoFs: 125646
Homozygous LoFs: 0
Heterozygous LoFs: 102
Defined: 125748
p: 0.000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0654	390	394	0.991	0.0000246	4316
Missense (PolyPhen)		154	183.64	0.83859		2009
Synonymous	-2.22	179	145	1.24	0.00000904	1267
Loss of Function	2.95	15	33.4	0.449	0.00000182	394

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0.0039	0.0039	notable
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00030	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting.;
Disease: DISEASE: Brugada syndrome 4 (BRGDA4) [MIM:611876]: A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:17224476}. Note=The gene represented in this entry may be involved in disease pathogenesis.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.0128
RVIS EVS: -0.71
RVIS percentile EVS: 14.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.225

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium