rs200098356

chr12-1860203-G-Achr12-1860203-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_172364.5(CACNA2D4):c.1882C>T(p.Arg628Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,613,112 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00034 (7 hom.)
• Consequence: CACNA2D4 NM_172364.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 2.45

Genes affected

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) 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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_172364.5 Downstream stopcodon found after 4 codons.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.1882C>T	p.Arg628Ter	stop_gained	19/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.1882C>T	p.Arg628Ter	stop_gained	19/38	1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152214 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000780 AC: 194 AN: 248596 Hom.: 5 AF XY: 0.000815 AC XY: 110 AN XY: 134918

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000656

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000342 AC: 500 AN: 1460780 Hom.: 7 Cov.: 31 AF XY: 0.000394 AC XY: 286 AN XY: 726710

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152332 Hom.: 1 Cov.: 34 AF XY: 0.000416 AC XY: 31 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000665 Hom.: 2

Bravo AF: 0.000419

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000603 AC: 5

ExAC AF: 0.000554 AC: 67

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinal cone dystrophy 4 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2014	The p.Arg628X variant in CACNA2D4 has not been previously reported in individuals with disease but has been identified in 0.06% (5/8296) of European American chromosomes and 0.03% (1/3876) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200098356). This nonsense variant leads to a premature termination codon at position 628 which is predicted to lead to a truncated or absent protein. Complete loss of CACNA2D4 function has been reported in 2 siblings with autosomal recessive retinal cone dystrophy and a mouse model with complete loss of Cacna2d4 function displayed code-rod dysfunction (Wycisk 2006). In summary while the case report and mouse model indicate loss of CACNA2D4 function may be associated with retinal cone dystrophy, more data is needed to establish the role of CACNA2D4 in disease and therefore the clinical significance of the p.Arg628X variant is uncertain. -

Abnormality of the eye Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

Undetermined rare ocular disorder with frequency of less than eight patients -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.38
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200098356; hg19: chr12-1969369; COSMIC: COSV54944470;