CACNB4

protein-coding

calcium voltage-gated channel auxiliary subunit beta 4, the group of Calcium voltage-gated channel auxiliary beta subunits|Membrane associated guanylate kinases

Gene summary

This gene encodes a member of the beta subunit family of voltage-dependent calcium channel complex proteins. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. The protein encoded by this locus plays an important role in calcium channel function by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Certain mutations in this gene have been associated with idiopathic generalized epilepsy (IGE), juvenile myoclonic epilepsy (JME), and episodic ataxia, type 5. [provided by RefSeq, Aug 2016]

MANE transcript

NM_000726.5

Inheritance

ClinVar variants

P:3U:121B:57

Top phenotype

Episodic ataxia, type 5

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr2:151,832,771-152,099,167

External References & Databases

Ensembl (ENSG00000182389)

Transcript & Mutation Effects

hg38 • Region Span ~266.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

The *CACNB4* gene encodes the beta-4 subunit of voltage-gated calcium channel complex proteins. In available literature, variants in *CACNB4* have been reported in relation to episodic ataxia type 5, juvenile myoclonic epilepsy, and idiopathic generalized epilepsy. This gene was originally analyzed in June 2018 and was disputed at the time of curation due to a lack of clinical evidence to support the gene-disease relationship. In July 2022, *CACNB4* was recurated by the ClinGen Epilepsy Gene Curation Expert Panel. Since the original curation, contradictory evidence has emerged. In 2019, Heyne et al (PMID:31056551) evaluated variants reportedly associated with neurodevelopmental disorders that were also included on gene panels targeted for epilepsy from 2013 to 2017. Authors compared variant frequencies of the genes compared to controls. As a result, *CACNB4* showed identical frequencies of ultra-rare variants in cases compared to the controls. This evidence demonstrates that removing a gene with no diagnostic yield, such as *CACNB4*, from panels would increase diagnostic yield over time and this publication has been utilized as evidence to refute remaining evidence in addition to the other reasons described in more detail below. The available genetic evidence for the gene-disease relationship between *CACNB4* and epilepsy phenotypes includes 7 probands across 4 publications (PMIDs:10762541, 18755274, 27959697, 32042491). However, all genetic evidence has been discarded. In three cases (PMID:10762541), confirmation selective gel electrophoresis (CSGE) was used to identify variants in *CACNB4*. CSGE is a screening method used to detect variation in only the gene of interest; therefore, there is no way to confirm that the probands did not have another genetic cause to explain their phenotype. In two cases (PMIDs:18755274, 27959697), another variant was identified in a known disease-causing gene. And in two cases (PMID:32042491), there is greater than one individual present in gnomAD (v2.1.1). Experimental evidence is also available in the literature including protein interaction, functional alteration, and a mouse model; however, in the absence of genetic evidence, no experimental evidence will be counted. In summary, the evidence supporting the relationship between *CACNB4* and autosomal dominant epilepsy has been updated to refuted following recuration and no valid evidence remains. New evidence would be needed to support this claim. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on July 5, 2022 (SOP Version 9).

juvenile myoclonic epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009696

Submitter: Orphanet

epilepsy, idiopathic generalized, susceptibility to, 9LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011892

Submitter: Labcorp Genetics (formerly Invitae)

epilepsy, idiopathic generalized, susceptibility to, 9LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011892

Submitter: G2P

episodic ataxia type 5SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013464

Submitter: Orphanet

Clinical Genomic Database (CGD)

Episodic ataxia, type 5AD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Individuals may manifest with recurrent attacks of vertigo and ataxia, and treatment with acetazolamide has been reported as being effective

Comments: Variants may modify seizure-related conditions due to variants in other genes (eg, SCN1A)

Refs: 10762541; 16100538; 18755274; 20301317

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNB4 variants in ClinVar

10 Conditions Cataloged

not specifiedTotal: 97

Idiopathic generalized epilepsyTotal: 94

not providedTotal: 92

Episodic ataxia type 5Total: 24

Epilepsy, idiopathic generalized, susceptibility to, 9Total: 18

CACNB4-related disorderTotal: 17

EpilepsyTotal: 1

Spastic ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000726.5. 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			6 clinvar	44 clinvar	2 clinvar	52
missense		2 clinvar	109 clinvar	11 clinvar		122
nonsense			3 clinvar			3
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	2	121	55	2	181

Highest pathogenic variant AF is 6.841574e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 105 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000726.5	RefSeq	NP_000717.2	14	MANE Select
ENST00000539935.7	Ensembl	ENSP00000438949.1	14	MANE Select
NM_001005746.4	RefSeq	NP_001005746.1	14	Standard
NM_001005747.4	RefSeq	NP_001005747.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cacnb4a	Danio rerio	Structure: whole organism Quality: dead abnormal

Gene / Model

Organism

Observed Phenotype

cacnb4a

Danio rerio

Structure: whole organism

Quality: dead

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
membrane depolarization
calcium ion transmembrane transport
regulation of voltage-gated calcium channel activity

Molecular Function

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

Cellular Component

cytosol
plasma membrane
voltage-gated calcium channel complex
cytoplasmic side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000539935
Coding exons: 14
Length: 266304
Individuals with no LoFs: 124641
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124655
p: 0.0000562

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.69	161	290	0.555	0.0000163	3367
Missense (PolyPhen)		62	141.13	0.43932		1620
Synonymous	0.863	95	106	0.894	0.00000604	1008
Loss of Function	3.77	9	32.0	0.281	0.00000187	347

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000057	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000090	0.000088	rare
South Asian	0.000067	0.000065	rare
Other	0	0.0	absent

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. {ECO:0000269|PubMed:11880487}.;
Disease: DISEASE: Juvenile myoclonic epilepsy 6 (EJM6) [MIM:607682]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269|PubMed:10762541}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Episodic ataxia 5 (EA5) [MIM:613855]: A disorder characterized by episodes of vertigo and ataxia that last for several hours. Interictal examination show spontaneous downbeat and gaze-evoked nystagmus, mild dysarthria and truncal ataxia. {ECO:0000269|PubMed:10762541}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.290
RVIS EVS: 0.08
RVIS percentile EVS: 60.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.764

Gene Damage Prediction

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