Genetic Variant CACNA2D1:c.2780+152A>G (chr7-81963904-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000722.4(CACNA2D1):c.2780+152A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 669,750 control chromosomes in the GnomAD database, including 16,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.23 ( 4146 hom., cov: 32)

Exomes 𝑓: 0.22 ( 12413 hom. )

Consequence

CACNA2D1
NM_000722.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0690

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 7-81963904-T-C is Benign according to our data. Variant chr7-81963904-T-C is described in ClinVar as Benign. ClinVar VariationId is 1226323.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.2780+152A>G		intron_variant	Intron 34 of 38	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.2780+152A>G		intron_variant	Intron 34 of 38	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34763

AN:

151814

Hom.:

4139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.278

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.195

Gnomad EAS

AF:

0.194

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.243

GnomAD4 exome

AF:

0.215

AC:

111498

AN:

517818

Hom.:

12413

AF XY:

0.214

AC XY:

59355

AN XY:

277172

show subpopulations

African (AFR)

AF:

0.285

AC:

3811

AN:

13376

American (AMR)

AF:

0.204

AC:

4970

AN:

24394

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

3002

AN:

15876

East Asian (EAS)

AF:

0.241

AC:

7540

AN:

31282

South Asian (SAS)

AF:

0.216

AC:

10901

AN:

50470

European-Finnish (FIN)

AF:

0.200

AC:

8818

AN:

44084

Middle Eastern (MID)

AF:

0.223

AC:

467

AN:

2092

European-Non Finnish (NFE)

AF:

0.214

AC:

65954

AN:

308304

Other (OTH)

AF:

0.216

AC:

6035

AN:

27940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

4490

8980

13471

17961

22451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.229

AC:

34799

AN:

151932

Hom.:

4146

Cov.:

AF XY:

0.228

AC XY:

16959

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.278

AC:

11543

AN:

41454

American (AMR)

AF:

0.216

AC:

3287

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

676

AN:

3462

East Asian (EAS)

AF:

0.194

AC:

1000

AN:

5146

South Asian (SAS)

AF:

0.238

AC:

1147

AN:

4826

European-Finnish (FIN)

AF:

0.205

AC:

2177

AN:

10596

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.209

AC:

14216

AN:

67910

Other (OTH)

AF:

0.241

AC:

510

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1354

2708

4063

5417

6771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.207

Hom.:

393

Bravo

AF:

0.234

Asia WGS

AF:

0.207

AC:

718

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.0

(source)

DANN

Benign

0.36

PhyloP100

-0.069

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

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