rs7966806

Positions:

chr12-1879001-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000382722.10(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
ENST00000382722.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.24

Variant links:

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]

CACNA2D4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CACNA2D4	NM_172364.5 linkuse as main transcript	c.1599A>G	p.Ser533=	synonymous_variant	15/38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.1599A>G	p.Ser533=	synonymous_variant	15/38	1	NM_172364.5	ENSP00000372169	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23764

AN:

151978

Hom.:

2643

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.106

AC XY:

77120

AN XY:

726620

show subpopulations

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.:

AF XY:

0.152

AC XY:

11342

AN XY:

74374

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over