rs7966806

chr12-1879001-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_172364.5(CACNA2D4):c.1599A>G(p.Ser533=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,612,812 control chromosomes in the GnomAD database, including 12,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2659 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9387 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.24

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-1879001-T-C is Benign according to our data. Variant chr12-1879001-T-C is described in ClinVar as [Benign]. Clinvar id is 262810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.1599A>G	p.Ser533=	synonymous_variant	15/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.1599A>G	p.Ser533=	synonymous_variant	15/38	1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23764 AN: 151978 Hom.: 2643 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0839

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.107 AC: 26590 AN: 248620 Hom.: 1896 AF XY: 0.107 AC XY: 14403 AN XY: 134960

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0332

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.0892

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.106 AC: 155005 AN: 1460716 Hom.: 9387 Cov.: 31 AF XY: 0.106 AC XY: 77120 AN XY: 726620

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.0560

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0890

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.157 AC: 23828 AN: 152096 Hom.: 2659 Cov.: 32 AF XY: 0.152 AC XY: 11342 AN XY: 74374

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.0836

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.0304

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0814

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.118

Alfa AF: 0.125 Hom.: 851

Bravo AF: 0.159

Asia WGS AF: 0.124 AC: 428 AN: 3478

EpiCase AF: 0.0982

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Retinal cone dystrophy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	4.9
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7966806; hg19: chr12-1988167; COSMIC: COSV54947144; COSMIC: COSV54947144;