CACNA2D4

protein-coding

calcium voltage-gated channel auxiliary subunit alpha2delta 4, the group of Calcium voltage-gated channel auxiliary alpha2delta subunits

Gene summary

This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. 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. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_172364.5

Inheritance

AR, AD

ClinVar variants

P:38U:684B:306

Top phenotype

Retinal cone dystrophy 4

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr12:1,791,963-1,918,666

External References & Databases

Ensembl (ENSG00000151062)

Transcript & Mutation Effects

hg38 • Region Span ~126.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinal cone dystrophy 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012507

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.

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

retinal cone dystrophy 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012507

Submitter: Labcorp Genetics (formerly Invitae)

CACNA2D4-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700244

Submitter: ClinGen

Variants in *CACNA2D4* were first associated with autosomal recessive inheritance of retinal cone dystrophy (RCD4) in 2006 (Wycisk et al., 17033974). Over eight probands reported four homozygous variants in this gene including one missense variant, and two large deletions covering multiple exons, as well as one stop gained. This gene-disease association is supported by expression throughout the inner nuclear layer of the retina, photoreceptors and retinal periphery in model organism, zebrafish by RNA *in situ* hybridization (Schlegel et al., 31834350). Additional functional studies show alterations in *Cacna2d4* in mice have significantly reduced transcript levels in the retina leading to structural and functional abnormalities of retinal ribbon synapses including substantial loss of photoreceptor activities and photoreceptor cell death (Wycisk et al., 16877424). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12.0 pts.) has been reached. In summary, *CACNA2D4* is definitively associated with autosomal recessive inheritance of CACNA2D4-related retinopathy, and this has been has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on March 2nd, 2023 (SOP Version 9).

retinal cone dystrophy 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012507

Submitter: G2P

Clinical Genomic Database (CGD)

Retinal cone dystrophy 4AR

Manifestation: Ophthalmologic

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

Refs: 17033974

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA2D4 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 1239

not specifiedTotal: 247

Inborn genetic diseasesTotal: 180

Retinal cone dystrophy 4Total: 112

CACNA2D4-related disorderTotal: 51

Retinal dystrophyTotal: 12

Optic atrophyTotal: 2

Retinal disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_172364.5. 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			15 clinvar	257 clinvar	3 clinvar	275
missense			608 clinvar	39 clinvar	7 clinvar	654
nonsense	1 clinvar	12 clinvar	18 clinvar			31
start loss			3 clinvar			3
frameshift	1 clinvar	12 clinvar	15 clinvar			28
splice donor/acceptor (+/-2bp)		12 clinvar	25 clinvar			37
Total	2	36	684	296	10	1028

Highest pathogenic variant AF is 0.0008479325

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_172364.5	RefSeq	NP_758952.4	38	MANE Select
ENST00000382722.10	Ensembl	ENSP00000372169.4	38	MANE Select
ENST00000444595.6	Ensembl	ENSP00000403371.2	17	Standard
ENST00000536846.6	Ensembl	ENSP00000468167.1	12	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

regulation of ion transmembrane transport
detection of light stimulus involved in visual perception
calcium ion transmembrane transport

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: ENST00000382722
Coding exons: 38
Length: 126880
Individuals with no LoFs: 124410
Homozygous LoFs: 6
Heterozygous LoFs: 456
Defined: 124872
p: 0.00185

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.752	628	683	0.919	0.0000416	7405
Missense (PolyPhen)		135	151.29	0.89235		1639
Synonymous	0.407	281	290	0.970	0.0000203	2154
Loss of Function	1.47	60	73.6	0.816	0.00000391	784

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0011	notable
Latino/Admixed American	0.00090	0.00090	rare
Ashkenazi Jewish	0.015	0.015	notable
East Asian	0.0020	0.0020	notable
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.0016	0.0016	notable
South Asian	0.0012	0.0012	notable
Other	0.0027	0.0025	notable

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. {ECO:0000269|PubMed:12181424}.;
Disease: DISEASE: Retinal cone dystrophy 4 (RCD4) [MIM:610478]: Characterized by minimal symptoms except for slowly progressive reduction in visual acuity. {ECO:0000269|PubMed:17033974}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.129

Intolerance Scores

LoFtool: 0.722
RVIS EVS: 0.93
RVIS percentile EVS: 89.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.202

Gene Damage Prediction

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