CACNA2D2

protein-coding

calcium voltage-gated channel auxiliary subunit alpha2delta 2, the group of Calcium voltage-gated channel auxiliary alpha2delta subunits

Gene summary

Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

MANE transcript

NM_006030.4

Inheritance

ClinVar variants

P:80U:442B:353

Top phenotype

Cerebellar atrophy with seizures and variable developmental delay

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr3:50,362,613-50,504,244

External References & Databases

Ensembl (ENSG00000007402)

Transcript & Mutation Effects

hg38 • Region Span ~141.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar atrophy with seizures and variable developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032788

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar atrophy with seizures and variable developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032788

Submitter: Ambry Genetics

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

Biallelic *CACNA2D2* variants were first reported in individuals with epilepsy, global developmental delay, and cerebellar atrophy in 2013 (Edvardson et al., PMID: 23339110). Some patients with biallelic variants in *CACNA2D2* have also been reported with motor features like ataxia, dysmetria, and dysarthria in addition to seizures and cerebellar atrophy (PMID: 31402629, 30410802). Given the broad neurodevelopmental phenotypes present in these individuals, we have chosen to curate this gene-disease relationship under the disease term complex neurodevelopmental disorder (MONDO:0100038). Ten variants (two frameshift, one synonymous, and seven missense) reported in eight probands across seven publications are included in this curation (PMIDs: 23339110, 24358150, 29997391, 30410802, 31402629, 33798445, 31130284). Of note, one individual with compound heterozygous missense and synonymous variants in *CACNA2D2* was not scored, as the phase of their variants was not confirmed (PMID: 33798445). This gene-disease relationship is also supported by two mouse models (PMIDs: 11756448, 14660671). In summary, there is moderate evidence to support the relationship between *CACNA2D2* and autosomal recessive complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on November 21, 2023 (SOP version 10).

Clinical Genomic Database (CGD)

Cerebellar atrophy with seizures and variable developmental delayAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 23339110; 29997391

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA2D2 variants in ClinVar

8 Conditions Cataloged

Early-infantile DEETotal: 968

Developmental and epileptic encephalopathyTotal: 206

Inborn genetic diseasesTotal: 134

not providedTotal: 84

not specifiedTotal: 76

Cerebellar atrophy with seizures and variable developmental delayTotal: 52

CACNA2D2-related disorderTotal: 22

Epileptic encephalopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006030.4. 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			9 clinvar	334 clinvar	1 clinvar	344
missense	2 clinvar	2 clinvar	421 clinvar	16 clinvar	2 clinvar	443
nonsense	11 clinvar	6 clinvar	4 clinvar			21
start loss						0
frameshift	33 clinvar	3 clinvar	3 clinvar			39
splice donor/acceptor (+/-2bp)	2 clinvar	21 clinvar	5 clinvar			28
Total	48	32	442	350	3	875

Highest pathogenic variant AF is 0.000006574017

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006030.4	RefSeq	NP_006021.2	38	MANE Select
ENST00000424201.7	Ensembl	ENSP00000390329.2	38	MANE Select
NM_001005505.3	RefSeq	NP_001005505.1	38	Standard
NM_001174051.3	RefSeq	NP_001167522.1	39	Standard

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

neuromuscular junction development
regulation of ion transmembrane transport
regulation of multicellular organism growth
positive regulation of organ growth
muscle fiber development

Molecular Function

voltage-gated calcium channel activity
metal ion binding

Cellular Component

plasma membrane
voltage-gated calcium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000479441
Coding exons: 39
Length: 141443
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125743
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.00	426	639	0.666	0.0000370	7495
Missense (PolyPhen)		134	269.56	0.49711		3042
Synonymous	-0.375	269	261	1.03	0.0000161	2208
Loss of Function	6.89	10	74.0	0.135	0.00000358	822

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000070	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosis. {ECO:0000269|PubMed:12555074, ECO:0000269|PubMed:15111129}.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.560
RVIS EVS: -0.55
RVIS percentile EVS: 19.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.184

Gene Damage Prediction

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