CACNA1B

protein-coding

calcium voltage-gated channel subunit alpha1 B, the group of Calcium voltage-gated channel alpha1 subunits|EF-hand domain containing

Gene summary

The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

Previous symbols:

CACNL1A5

MANE transcript

NM_000718.4

Inheritance

AR, AD

ClinVar variants

P:61U:678B:659

Top phenotype

Dystonia 23

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr9:137,877,782-138,124,624

External References & Databases

Ensembl (ENSG00000148408)

Transcript & Mutation Effects

hg38 • Region Span ~246.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movementsLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032784

Submitter: Ambry Genetics

neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movementsMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032784

Submitter: Illumina

neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movementsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032784

Submitter: G2P

complex neurodevelopmental disorder with motor featuresMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100516

Submitter: ClinGen

*CACNA1B* encodes the (α1B) pore-forming subunit of the N-type voltage-gated calcium channel. *CACNA1B* was first reported in relation to autosomal recessive complex neurodevelopmental disorder with motor features in 2019 (Gorman KM et al., PMID: 30982612). Four variants have been reported in 6 children from 3 unrelated families, in one publication; all probands presented with early onset epileptic encephalopathy, severe neurodevelopmental delay with regression, and hyperkinetic movement disorder (PMID: 30982612). A different publication reported on a proband with a compound deep intronic splicing variant and missense variant. However, due to the high variant frequencies in gnomAD, the pathogenicity of these variants is unclear and these were not scored (PMID: 37095367). To date, no experimental evidence supports the relationship between *CACNA1B* and AR complex neurodevelopmental disorder with motor features. In summary, there is MODERATE evidence to support this gene-disease relationship. The ClinGen Cerebral Palsy Working Group approved this classification on August 21, 2023 (SOP Version 9).

neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movementsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032784

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Clinical Genomic Database (CGD)

Dystonia 23AD

Manifestation: Cardiovascular; Neurologic

Intervention: Cardiovascular

Rationale: As the condition can include cardiac arrhythmias, awareness may allow surveillance and early management

Refs: 21370267; 25296916; 30982612

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA1B variants in ClinVar

9 Conditions Cataloged

not providedTotal: 1617

not specifiedTotal: 514

CACNA1B-related disorderTotal: 78

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movementsTotal: 74

Dystonia 23Total: 6

See casesTotal: 3

Complex neurodevelopmental disorder with motor featuresTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000718.4. 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	596 clinvar	7 clinvar	608
missense			647 clinvar	50 clinvar	2 clinvar	699
nonsense	14 clinvar	6 clinvar	1 clinvar			21
start loss			2 clinvar			2
frameshift	20 clinvar	5 clinvar	7 clinvar	1 clinvar		33
splice donor/acceptor (+/-2bp)	1 clinvar	15 clinvar	16 clinvar	3 clinvar		35
Total	35	26	678	650	9	1398

Highest pathogenic variant AF is 0.000006956416

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000718.4	RefSeq	NP_000709.1	47	MANE Select
ENST00000371372.6	Ensembl	ENSP00000360423.1	47	MANE Select
NM_001243812.2	RefSeq	NP_001230741.1	47	Standard
ENST00000277551.6	Ensembl	ENSP00000277551.2	47	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)
Serotonergic synapse - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)

Biological Process

calcium ion transport
chemical synaptic transmission
neurotransmitter secretion
locomotory behavior
regulation of heart contraction

Molecular Function

amyloid-beta binding
voltage-gated calcium channel activity
calcium channel activity
calcium ion binding
protein binding

Cellular Component

plasma membrane
voltage-gated calcium channel complex
dendrite
neuronal cell body
presynapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371372
Coding exons: 47
Length: 246836
Individuals with no LoFs: 117913
Homozygous LoFs: 0
Heterozygous LoFs: 6765
Defined: 124678
p: 0.0275

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.52	841	1.30e+3	0.647	0.0000821	15050
Missense (PolyPhen)		198	375.01	0.52799		4039
Synonymous	-0.416	546	534	1.02	0.0000348	4663
Loss of Function	7.85	16	101	0.158	0.00000526	1179

Population LoF Frequency

Population	CAF	p-value	Status
African	0.024	0.021	notable
Latino/Admixed American	0.026	0.021	notable
Ashkenazi Jewish	0.056	0.045	notable
East Asian	0.019	0.017	notable
Finnish	0.027	0.022	notable
European (Non-Finnish)	0.035	0.030	notable
South Asian	0.044	0.036	notable
Other	0.029	0.025	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. The isoform alpha-1B gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by omega-conotoxin-GVIA (AC P01522) (AC P01522) (By similarity). They are however insensitive to dihydropyridines (DHP). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons. {ECO:0000250|UniProtKB:Q02294}.;
Disease: DISEASE: Dystonia 23 (DYT23) [MIM:614860]: A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT23 is an autosomal dominant dystonia affecting the face, neck, limbs. Some DYT23 patients manifest generalized myoclonus in addition to progressive action-induced multifocal dystonia. {ECO:0000269|PubMed:25296916}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.215

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.892

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High