CACNA2D4

Chr 12AR

calcium voltage-gated channel auxiliary subunit alpha2delta 4

Also known as: RCD4

NCBI Gene: 93589 ENSG00000151062 UniProt: Q7Z3S7 OMIM: 608171

The alpha-2/delta-4 subunit regulates calcium current density and activation/inactivization kinetics of voltage-dependent calcium channels, which mediate calcium influx upon membrane depolarization. Biallelic mutations cause retinal cone dystrophy 4, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to haploinsufficiency in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.011 OMIM phenotype

Clinical Summary— CACNA2D4

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Gene-Disease Validity (ClinGen)

CACNA2D4-related retinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 824 VUS of 1430 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.01LOEUF

pLI 0.000

Z-score 1.47

OE 0.82 (0.66–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.75Z-score

OE missense 0.92 (0.86–0.98)

628 obs / 683.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.66–1.01)

0≤0.351.4

Missense OE?0.92 (0.86–0.98)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 60 / 73.6Missense obs/exp: 628 / 683.3Syn Z: 0.41

ClinVar Variant Classifications

1430 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic4

VUS824

Likely Benign465

Benign64

Conflicting58

Pathogenic

Likely Pathogenic

824

VUS

465

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	3	0	5
Likely Pathogenic	3	0	1	0	4
VUS	69	635	109	11	824
Likely Benign	0	18	224	223	465
Benign	0	11	40	13	64
Conflicting	—				58
Total	74	664	377	247	1,420

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

70 pathogenic / likely-pathogenic (of 98) ClinVar copy-number / structural variants overlap CACNA2D4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →