rs758160

Positions:

• chr12-1874616-C-T

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.1866G>A​(p.Pro622=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,610,304 control chromosomes in the GnomAD database, including 8,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (995 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7727 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.73

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=-0.69).
• BP6: Variant 12-1874616-C-T is Benign according to our data. Variant chr12-1874616-C-T is described in ClinVar as [Benign]. Clinvar id is 262811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.1866G>A	p.Pro622=	synonymous_variant	18/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.1866G>A	p.Pro622=	synonymous_variant	18/38	1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16012 AN: 152094 Hom.: 986 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.0935 AC: 23288 AN: 249116 Hom.: 1257 AF XY: 0.0964 AC XY: 13024 AN XY: 135130

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0330

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.0831

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0965

GnomAD4 exome AF: 0.0995 AC: 145090 AN: 1458092 Hom.: 7727 Cov.: 29 AF XY: 0.100 AC XY: 72804 AN XY: 725546

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.0462

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.105 AC: 16054 AN: 152212 Hom.: 995 Cov.: 32 AF XY: 0.102 AC XY: 7587 AN XY: 74422

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0642

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0303

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0745

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.0908

Alfa AF: 0.100 Hom.: 1097

Bravo AF: 0.103

Asia WGS AF: 0.115 AC: 399 AN: 3478

EpiCase AF: 0.0981

EpiControl AF: 0.101

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 12, 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	-0.69
CADD	Benign	0.95
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs758160; hg19: chr12-1983782; COSMIC: COSV54947136;