7-82136680-CAA-CA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000722.4(CACNA2D1):c.355-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,292,524 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0050 ( 1 hom. )

Consequence

CACNA2D1
NM_000722.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0210

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 -8 ACMG points.

BP6

Variant 7-82136680-CA-C is Benign according to our data. Variant chr7-82136680-CA-C is described in ClinVar as Benign. ClinVar VariationId is 221019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.355-5delT		splice_region_variant, intron_variant	Intron 4 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.355-5delT		splice_region_variant, intron_variant	Intron 4 of 38	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

139182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000727

Gnomad ASJ

AF:

0.000305

Gnomad EAS

AF:

0.000413

Gnomad SAS

AF:

0.000454

Gnomad FIN

AF:

0.000486

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000173

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0145

AC:

1693

AN:

116500

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.00746

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.00499

AC:

5760

AN:

1153250

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

2843

AN XY:

571038

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00587

AC:

156

AN:

26592

American (AMR)

AF:

0.00814

AC:

253

AN:

31086

Ashkenazi Jewish (ASJ)

AF:

0.00298

AC:

AN:

19792

East Asian (EAS)

AF:

0.00182

AC:

AN:

30734

South Asian (SAS)

AF:

0.00650

AC:

409

AN:

62970

European-Finnish (FIN)

AF:

0.00546

AC:

199

AN:

36470

Middle Eastern (MID)

AF:

0.00423

AC:

AN:

4724

European-Non Finnish (NFE)

AF:

0.00494

AC:

4411

AN:

893722

Other (OTH)

AF:

0.00418

AC:

197

AN:

47160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.253

Heterozygous variant carriers

837

1675

2512

3350

4187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

192

384

576

768

960

<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:

0.000194

AC:

AN:

139274

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

67300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000131

AC:

AN:

38256

American (AMR)

AF:

0.000145

AC:

AN:

13778

Ashkenazi Jewish (ASJ)

AF:

0.000305

AC:

AN:

3284

East Asian (EAS)

AF:

0.000414

AC:

AN:

4834

South Asian (SAS)

AF:

0.000456

AC:

AN:

4388

European-Finnish (FIN)

AF:

0.000486

AC:

AN:

8232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000173

AC:

AN:

63436

Other (OTH)

AF:

0.00

AC:

AN:

1912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0159

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 21, 2019

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

PhyloP100

0.021

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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