7-82066526-TAAAAAAA-TAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000722.4(CACNA2D1):c.659-4_659-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,348,660 control chromosomes in the GnomAD database, including 56 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 55 hom., cov: 27)

Exomes 𝑓: 0.031 ( 1 hom. )

Consequence

CACNA2D1
NM_000722.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.23

Publications

3 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
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
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
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 -16 ACMG points.

BP6

Variant 7-82066526-TAA-T is Benign according to our data. Variant chr7-82066526-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 518490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D1	NM_000722.4	MANE Select	c.659-4_659-3delTT	splice_region intron	N/A	NP_000713.2	P54289-2
CACNA2D1	NM_001366867.1		c.659-4_659-3delTT	splice_region intron	N/A	NP_001353796.1	P54289-1
CACNA2D1	NM_001302890.2		c.659-4_659-3delTT	splice_region intron	N/A	NP_001289819.1	E7ERK3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.659-4_659-3delTT	splice_region intron	N/A	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000423588.1	TSL:1	c.659-4_659-3delTT	splice_region intron	N/A	ENSP00000405395.1	E7ERK3
CACNA2D1	ENST00000443883.2	TSL:5	c.659-4_659-3delTT	splice_region intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

2346

AN:

111648

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00650

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000257

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00488

Gnomad MID

AF:

0.00909

Gnomad NFE

AF:

0.000602

Gnomad OTH

AF:

0.0184

GnomAD2 exomes

AF:

0.0775

AC:

7016

AN:

90532

AF XY:

0.0777

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.0938

Gnomad ASJ exome

AF:

0.0760

Gnomad EAS exome

AF:

0.0757

Gnomad FIN exome

AF:

0.0531

Gnomad NFE exome

AF:

0.0667

Gnomad OTH exome

AF:

0.0756

GnomAD4 exome

AF:

0.0306

AC:

37912

AN:

1237034

Hom.:

AF XY:

0.0318

AC XY:

19387

AN XY:

610022

show subpopulations

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

African (AFR)

AF:

0.0892

AC:

2413

AN:

27058

American (AMR)

AF:

0.0745

AC:

2050

AN:

27528

Ashkenazi Jewish (ASJ)

AF:

0.0455

AC:

984

AN:

21636

East Asian (EAS)

AF:

0.0431

AC:

1389

AN:

32244

South Asian (SAS)

AF:

0.0563

AC:

3621

AN:

64260

European-Finnish (FIN)

AF:

0.0507

AC:

1835

AN:

36186

Middle Eastern (MID)

AF:

0.0371

AC:

144

AN:

3884

European-Non Finnish (NFE)

AF:

0.0242

AC:

23596

AN:

973292

Other (OTH)

AF:

0.0369

AC:

1880

AN:

50946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.266

Heterozygous variant carriers

4312

8625

12937

17250

21562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.0210

AC:

2347

AN:

111626

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1124

AN XY:

52912

show subpopulations

African (AFR)

AF:

0.0649

AC:

2193

AN:

33812

American (AMR)

AF:

0.00650

AC:

AN:

10468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2614

East Asian (EAS)

AF:

0.000258

AC:

AN:

3870

South Asian (SAS)

AF:

0.00

AC:

AN:

3484

European-Finnish (FIN)

AF:

0.00488

AC:

AN:

5122

Middle Eastern (MID)

AF:

0.00990

AC:

AN:

202

European-Non Finnish (NFE)

AF:

0.000602

AC:

AN:

49808

Other (OTH)

AF:

0.0183

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

192

288

384

480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0385

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

CACNA2D1-related disorder (1)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over