7-82060535-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000722.4(CACNA2D1):c.780-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,531,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CACNA2D1
NM_000722.4 splice_region, intron

Scores

Splicing: ADA: 0.00005282

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.43

Publications

0 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-82060535-T-C is Benign according to our data. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82060535-T-C is described in CliVar as Likely_benign. Clinvar id is 532165.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.780-8A>G		splice_region_variant, intron_variant	Intron 9 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.780-8A>G		splice_region_variant, intron_variant	Intron 9 of 38	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.000753

AC:

114

AN:

151364

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.000164

AC:

AN:

249416

AF XY:

0.000119

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

160

AN:

1379536

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

690988

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

31870

American (AMR)

AF:

0.000112

AC:

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25442

East Asian (EAS)

AF:

0.00

AC:

AN:

39146

South Asian (SAS)

AF:

0.00

AC:

AN:

84534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51946

Middle Eastern (MID)

AF:

0.000179

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.0000539

AC:

AN:

1038928

Other (OTH)

AF:

0.000330

AC:

AN:

57564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000753

AC:

114

AN:

151480

Hom.:

Cov.:

AF XY:

0.000689

AC XY:

AN XY:

73968

show subpopulations

African (AFR)

AF:

0.00249

AC:

103

AN:

41360

American (AMR)

AF:

0.000132

AC:

AN:

15132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5026

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67904

Other (OTH)

AF:

0.000952

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000227

Hom.:

Bravo

AF:

0.000903

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome

Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA2D1-related disorder

Benign:1

Jun 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.9

(source)

DANN

Benign

0.65

PhyloP100

-1.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000053

dbscSNV1_RF

Benign

0.0040

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