rs1229502

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000722.4(CACNA2D1):c.3114C>T(p.Pro1038Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,606,426 control chromosomes in the GnomAD database, including 72,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5505 hom., cov: 32)

Exomes 𝑓: 0.30 ( 66514 hom. )

Consequence

CACNA2D1
NM_000722.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.215

Publications

12 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=-0.4).

BP6

Variant 7-81959320-G-A is Benign according to our data. Variant chr7-81959320-G-A is described in ClinVar as Benign. ClinVar VariationId is 256767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.215 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.3114C>T	p.Pro1038Pro	synonymous_variant	Exon 38 of 39	ENST00000356860.8	NP_000713.2	P54289-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D1	ENST00000356860.8 link	c.3114C>T	p.Pro1038Pro	synonymous_variant	Exon 38 of 39	1	NM_000722.4	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000443883.2 link	c.3150C>T	p.Pro1050Pro	synonymous_variant	Exon 38 of 39	5		ENSP00000409374.2	P54289-1H0Y715
CACNA2D1	ENST00000705962.1 link	c.2994C>T	p.Pro998Pro	synonymous_variant	Exon 37 of 38			ENSP00000516190.1	A0A994J595
CACNA2D1	ENST00000705961.1 link	c.2880C>T	p.Pro960Pro	synonymous_variant	Exon 36 of 37			ENSP00000516189.1	A0A994J5M8

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38638

AN:

151658

Hom.:

5504

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.310

Gnomad OTH

AF:

0.277

GnomAD2 exomes

AF:

0.291

AC:

72862

AN:

250768

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.290

GnomAD4 exome

AF:

0.299

AC:

435612

AN:

1454650

Hom.:

66514

Cov.:

AF XY:

0.300

AC XY:

217288

AN XY:

724108

show subpopulations

African (AFR)

AF:

0.128

AC:

4269

AN:

33370

American (AMR)

AF:

0.336

AC:

14997

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

8300

AN:

26048

East Asian (EAS)

AF:

0.281

AC:

11127

AN:

39638

South Asian (SAS)

AF:

0.290

AC:

24972

AN:

86096

European-Finnish (FIN)

AF:

0.290

AC:

15453

AN:

53366

Middle Eastern (MID)

AF:

0.295

AC:

1696

AN:

5744

European-Non Finnish (NFE)

AF:

0.305

AC:

337373

AN:

1105612

Other (OTH)

AF:

0.290

AC:

17425

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

13574

27148

40721

54295

67869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10964

21928

32892

43856

54820

<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:

0.255

AC:

38636

AN:

151776

Hom.:

5505

Cov.:

AF XY:

0.256

AC XY:

18954

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.136

AC:

5628

AN:

41468

American (AMR)

AF:

0.302

AC:

4590

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

1104

AN:

3468

East Asian (EAS)

AF:

0.234

AC:

1204

AN:

5140

South Asian (SAS)

AF:

0.276

AC:

1327

AN:

4810

European-Finnish (FIN)

AF:

0.287

AC:

3020

AN:

10538

Middle Eastern (MID)

AF:

0.274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.310

AC:

21002

AN:

67838

Other (OTH)

AF:

0.273

AC:

577

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1406

2812

4218

5624

7030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.294

Hom.:

6062

Bravo

AF:

0.250

Asia WGS

AF:

0.215

AC:

748

AN:

3478

EpiCase

AF:

0.310

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 28, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 19, 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

-0.40

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

0.21

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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