chr12-1840773-C-T

Position:

chr12-1840773-C-T

Variant summary

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

The NM_172364.5(CACNA2D4):c.2517G>A(p.Ala839=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,590 control chromosomes in the GnomAD database, including 10,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1798 hom., cov: 34)

Exomes 𝑓: 0.10 ( 8440 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -2.06

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=-0.54).

BP6

Variant 12-1840773-C-T is Benign according to our data. Variant chr12-1840773-C-T is described in ClinVar as [Benign]. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNA2D4	NM_172364.5 linkuse as main transcript	c.2517G>A	p.Ala839=	synonymous_variant	26/38	ENST00000382722.10	NP_758952.4
CACNA2D4	XM_011521041.3 linkuse as main transcript	c.2454G>A	p.Ala818=	synonymous_variant	25/36		XP_011519343.1
CACNA2D4	XM_047429897.1 linkuse as main transcript	c.2445G>A	p.Ala815=	synonymous_variant	25/36		XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.2517G>A	p.Ala839=	synonymous_variant	26/38	1	NM_172364.5	ENSP00000372169	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20652

AN:

152100

Hom.:

1794

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0875

Gnomad ASJ

AF:

0.0942

Gnomad EAS

AF:

0.0146

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.106

GnomAD3 exomes

AF:

0.104

AC:

25861

AN:

249110

Hom.:

1691

AF XY:

0.102

AC XY:

13788

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.0896

Gnomad ASJ exome

AF:

0.0916

Gnomad EAS exome

AF:

0.0141

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.107

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.103

AC:

149916

AN:

1461372

Hom.:

8440

Cov.:

AF XY:

0.102

AC XY:

74021

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.235

Gnomad4 AMR exome

AF:

0.0892

Gnomad4 ASJ exome

AF:

0.0946

Gnomad4 EAS exome

AF:

0.0131

Gnomad4 SAS exome

AF:

0.103

Gnomad4 FIN exome

AF:

0.107

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.105

GnomAD4 genome

AF:

0.136

AC:

20696

AN:

152218

Hom.:

1798

Cov.:

AF XY:

0.133

AC XY:

9889

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.238

Gnomad4 AMR

AF:

0.0873

Gnomad4 ASJ

AF:

0.0942

Gnomad4 EAS

AF:

0.0149

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.105

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.117

Hom.:

573

Bravo

AF:

0.137

Asia WGS

AF:

0.0920

AC:

318

AN:

3478

EpiCase

AF:

0.0955

EpiControl

AF:

0.0971

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.54

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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