rs60945277

chr12-1879852-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.1515A>G(p.Thr505=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,600,736 control chromosomes in the GnomAD database, including 20,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5998 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14035 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.108

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=-0.65).
• BP6: Variant 12-1879852-T-C is Benign according to our data. Variant chr12-1879852-T-C is described in ClinVar as [Benign]. Clinvar id is 262809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.108 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.1515A>G	p.Thr505=	synonymous_variant	14/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.1515A>G	p.Thr505=	synonymous_variant	14/38	1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33035 AN: 151996 Hom.: 5967 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0348

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.128 AC: 29090 AN: 226974 Hom.: 2953 AF XY: 0.126 AC XY: 15443 AN XY: 122650

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.0671

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0332

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.0922

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.122 AC: 177390 AN: 1448620 Hom.: 14035 Cov.: 31 AF XY: 0.122 AC XY: 88086 AN XY: 719096

Gnomad4 AFR exome AF: 0.510

Gnomad4 AMR exome AF: 0.0708

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0561

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0924

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.218 AC: 33115 AN: 152116 Hom.: 5998 Cov.: 33 AF XY: 0.212 AC XY: 15766 AN XY: 74358

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0347

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.171

Alfa AF: 0.165 Hom.: 1453

Bravo AF: 0.228

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2016	- -

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	-0.65
Cadd	Benign	1.4
Dann	Benign	0.28

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: rs60945277; hg19: chr12-1989018; COSMIC: COSV54945801; COSMIC: COSV54945801;