CACNA2D4

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

Basic information

Region (hg38): 12:1791962-1918666

Links

ENSG00000151062 ∙ NCBI:93589 ∙ OMIM:608171 ∙ HGNC:20202 ∙ Uniprot:Q7Z3S7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• retinal cone dystrophy 4 (Moderate), mode of inheritance: AR
• cone-rod dystrophy (Supportive), mode of inheritance: AD
• retinal cone dystrophy 4 (Strong), mode of inheritance: AR
• retinal cone dystrophy 4 (Limited), mode of inheritance: Unknown
• inherited retinal dystrophy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Retinal cone dystrophy 4	AR	General	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	Ophthalmologic	17033974

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CACNA2D4 gene.

• not provided (930 variants)
• Retinal cone dystrophy 4 (182 variants)
• Inborn genetic diseases (70 variants)
• not specified (32 variants)
• Cone dystrophy 3 (11 variants)
• Retinal dystrophy (4 variants)
• Retinitis pigmentosa (1 variants)
• Progressive cone dystrophy (without rod involvement) (1 variants)
• CACNA2D4-related condition (1 variants)
• Abnormality of the eye (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA2D4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	158	13	178
missense			432	10	13	455
nonsense		1	16			17
start loss			3			3
frameshift			10			10
inframe indel			2	1		3
splice donor/acceptor (+/-2bp)			24			24
splice region			46	37	2	85
non coding			58	132	40	230
Total	0	1	552	301	66

Variants in CACNA2D4

This is a list of pathogenic ClinVar variants found in the CACNA2D4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-1791965-G-C		Retinal cone dystrophy 4	Uncertain significance (Jan 12, 2018)
12-1792021-T-A		Retinal cone dystrophy 4	Uncertain significance (Jan 12, 2018)
12-1792023-C-T		Retinal cone dystrophy 4	Uncertain significance (Jan 12, 2018)
12-1792031-C-G		Retinal cone dystrophy 4	Benign (Jan 12, 2018)
12-1792034-C-G		Retinal cone dystrophy 4	Uncertain significance (Jan 13, 2018)
12-1792040-C-G		Retinal cone dystrophy 4	Uncertain significance (Jan 12, 2018)
12-1792042-A-G		Retinal cone dystrophy 4	Uncertain significance (Jan 12, 2018)
12-1792058-C-G		Retinal cone dystrophy 4	Likely benign (Jan 12, 2018)
12-1792059-C-T		Retinal cone dystrophy 4	Benign (Jan 12, 2018)
12-1792083-C-G		Retinal cone dystrophy 4	Uncertain significance (Jan 13, 2018)
12-1792098-T-G		Retinal cone dystrophy 4	Benign (Jan 13, 2018)
12-1792099-A-G		Retinal cone dystrophy 4	Benign (Jan 13, 2018)
12-1792158-C-G		Retinal cone dystrophy 4	Uncertain significance (Jan 13, 2018)
12-1792167-G-A		Retinal cone dystrophy 4	Uncertain significance (Jan 13, 2018)
12-1792226-T-TCTC		Cone dystrophy 3	Benign (Jun 14, 2016)
12-1792252-G-C		Retinal cone dystrophy 4	Likely benign (Jan 13, 2018)
12-1792268-C-T		Retinal cone dystrophy 4	Benign (Jan 12, 2018)
12-1792291-A-G		Retinal cone dystrophy 4	Uncertain significance (Jan 13, 2018)
12-1792295-C-T		Retinal cone dystrophy 4	Benign (Jan 12, 2018)
12-1792319-G-T		Retinal cone dystrophy 4	Benign (Jan 13, 2018)
12-1792321-T-C		Retinal cone dystrophy 4	Likely benign (Jan 12, 2018)
12-1792380-A-C		Retinal cone dystrophy 4	Benign (Jan 13, 2018)
12-1792384-G-A		Retinal cone dystrophy 4	Uncertain significance (Jan 13, 2018)
12-1792410-A-T		Retinal cone dystrophy 4	Uncertain significance (Mar 23, 2018)
12-1792438-G-C		Retinal cone dystrophy 4	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CACNA2D4	protein_coding	protein_coding	ENST00000382722	38	126880

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.49e-34	0.00280	124410	6	456	124872	0.00185

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.752	628	683	0.919	0.0000416	7405
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00204	0.00198
Ashkenazi Jewish	0.0150	0.0146
East Asian	0.00202	0.00200
Finnish	0.000239	0.000232
European (Non-Finnish)	0.00158	0.00156
Middle Eastern	0.00202	0.00200
South Asian	0.00119	0.00118
Other	0.00265	0.00247

dbNSFP

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.
• Pathway: 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);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Arrhythmogenic Right Ventricular Cardiomyopathy;MAPK Signaling Pathway;Phase 0 - rapid depolarisation;Phase 2 - plateau phase;Cardiac conduction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.129

Intolerance Scores

• loftool: 0.722
• rvis_EVS: 0.93
• rvis_percentile_EVS: 89.66

Haploinsufficiency Scores

• pHI: 0.242
• hipred: N
• hipred_score: 0.275
• ghis: 0.443

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.202

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cacna2d4
• Phenotype: vision/eye phenotype

Gene ontology

• Biological process: regulation of ion transmembrane transport;detection of light stimulus involved in visual perception;calcium ion transmembrane transport
• Cellular component: plasma membrane;voltage-gated calcium channel complex
• Molecular function: voltage-gated calcium channel activity;metal ion binding