rs2229952

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000722.4(CACNA2D1):c.963G>A(p.Ala321Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,612,970 control chromosomes in the GnomAD database, including 1,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 160 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1390 hom. )

Consequence

CACNA2D1
NM_000722.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.78

Publications

6 publications found

Variant links:

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 Gene-Disease associations (from GenCC):

short QT syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
Brugada syndrome
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
developmental and epileptic encephalopathy 110
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNA2D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 7-82038152-C-T is Benign according to our data. Variant chr7-82038152-C-T is described in ClinVar as Benign. ClinVar VariationId is 256769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.78 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0347 (5288/152196) while in subpopulation NFE AF = 0.0489 (3326/68014). AF 95% confidence interval is 0.0475. There are 160 homozygotes in GnomAd4. There are 2611 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 160 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.963G>A	p.Ala321Ala	synonymous_variant	Exon 11 of 39	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 link	c.963G>A	p.Ala321Ala	synonymous_variant	Exon 11 of 39	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5282

AN:

152080

Hom.:

160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00824

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0539

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0316

Gnomad FIN

AF:

0.0698

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0489

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0375

AC:

9410

AN:

251086

AF XY:

0.0389

show subpopulations

Gnomad AFR exome

AF:

0.00609

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0527

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0676

Gnomad NFE exome

AF:

0.0473

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0400

AC:

58379

AN:

1460774

Hom.:

1390

Cov.:

AF XY:

0.0403

AC XY:

29268

AN XY:

726708

show subpopulations

African (AFR)

AF:

0.00634

AC:

212

AN:

33464

American (AMR)

AF:

0.0214

AC:

956

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0531

AC:

1386

AN:

26110

East Asian (EAS)

AF:

0.000126

AC:

AN:

39636

South Asian (SAS)

AF:

0.0342

AC:

2946

AN:

86242

European-Finnish (FIN)

AF:

0.0674

AC:

3592

AN:

53320

Middle Eastern (MID)

AF:

0.0450

AC:

259

AN:

5758

European-Non Finnish (NFE)

AF:

0.0422

AC:

46839

AN:

1111160

Other (OTH)

AF:

0.0362

AC:

2184

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2628

5256

7883

10511

13139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1594

3188

4782

6376

7970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0347

AC:

5288

AN:

152196

Hom.:

160

Cov.:

AF XY:

0.0351

AC XY:

2611

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00824

AC:

342

AN:

41514

American (AMR)

AF:

0.0218

AC:

333

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0539

AC:

187

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0325

AC:

157

AN:

4832

European-Finnish (FIN)

AF:

0.0698

AC:

739

AN:

10590

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0489

AC:

3326

AN:

68014

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

272

545

817

1090

1362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0465

Hom.:

124

Bravo

AF:

0.0285

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0435

EpiControl

AF:

0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 30, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Jun 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Brugada syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jun 11, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

2.2

(source)

DANN

Benign

0.75

PhyloP100

-2.8

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over