rs37133

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000722.4(CACNA2D1):c.1279T>C(p.Leu427Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,578,384 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L427L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 99 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 118 hom. )

Consequence

CACNA2D1
NM_000722.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.75

Publications

2 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 links:

CACNA2D1-AS1 (HGNC:40120): (CACNA2D1 antisense RNA 1)

CACNA2D1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 7-82012237-A-G is Benign according to our data. Variant chr7-82012237-A-G is described in ClinVar as Benign. ClinVar VariationId is 381781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.1279T>C	p.Leu427Leu	synonymous_variant	Exon 15 of 39	ENST00000356860.8	NP_000713.2	P54289-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 link	c.1279T>C	p.Leu427Leu	synonymous_variant	Exon 15 of 39	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3053

AN:

148268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0716

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00933

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.000638

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0136

Gnomad NFE

AF:

0.000593

Gnomad OTH

AF:

0.0178

GnomAD2 exomes

AF:

0.00587

AC:

1466

AN:

249652

AF XY:

0.00453

show subpopulations

Gnomad AFR exome

AF:

0.0718

Gnomad AMR exome

AF:

0.00511

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000638

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00241

AC:

3442

AN:

1430004

Hom.:

118

Cov.:

AF XY:

0.00212

AC XY:

1511

AN XY:

713242

show subpopulations

African (AFR)

AF:

0.0716

AC:

2328

AN:

32518

American (AMR)

AF:

0.00569

AC:

254

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39414

South Asian (SAS)

AF:

0.000912

AC:

AN:

85520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52684

Middle Eastern (MID)

AF:

0.00775

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.000394

AC:

427

AN:

1084464

Other (OTH)

AF:

0.00522

AC:

309

AN:

59240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0206

AC:

3060

AN:

148380

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1466

AN XY:

72330

show subpopulations

African (AFR)

AF:

0.0715

AC:

2841

AN:

39720

American (AMR)

AF:

0.00932

AC:

135

AN:

14486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000199

AC:

AN:

5036

South Asian (SAS)

AF:

0.000639

AC:

AN:

4696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.0145

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000593

AC:

AN:

67400

Other (OTH)

AF:

0.0176

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

139

277

416

554

693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00862

Hom.:

Bravo

AF:

0.0231

Asia WGS

AF:

0.0100

AC:

AN:

3476

EpiCase

AF:

0.000600

EpiControl

AF:

0.00125

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 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. -

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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 16, 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

-0.48

CADD

Benign

9.6

(source)

DANN

Benign

0.91

PhyloP100

2.8

Mutation Taster

=100/0

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

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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