Genetic Variant CACNA2D1:c.659-3delT (chr7-82066526-TA-T) – ACMG Classification: Benign (-16 pts)

Variant summary

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

The NM_000722.4(CACNA2D1):c.659-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 111,628 control chromosomes in the GnomAD database, including 240 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 240 hom., cov: 27)

Exomes 𝑓: 0.31 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CACNA2D1
NM_000722.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.04

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-TA-T is Benign according to our data. Variant chr7-82066526-TA-T is described in ClinVar as Benign. ClinVar VariationId is 416576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.659-3delT	splice_region intron	N/A	NP_000713.2	P54289-2
CACNA2D1	NM_001366867.1		c.659-3delT	splice_region intron	N/A	NP_001353796.1	P54289-1
CACNA2D1	NM_001302890.2		c.659-3delT	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.659-3delT	splice_region intron	N/A	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000423588.1	TSL:1	c.659-3delT	splice_region intron	N/A	ENSP00000405395.1	E7ERK3
CACNA2D1	ENST00000443883.2	TSL:5	c.659-3delT	splice_region intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

5259

AN:

111650

Hom.:

240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0275

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.0211

Gnomad SAS

AF:

0.00428

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.00736

Gnomad OTH

AF:

0.0288

GnomAD2 exomes

AF:

0.337

AC:

30495

AN:

90532

AF XY:

0.340

show subpopulations

Gnomad AFR exome

AF:

0.256

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.349

Gnomad EAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.358

Gnomad NFE exome

AF:

0.337

Gnomad OTH exome

AF:

0.342

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.311

AC:

346937

AN:

1116808

Hom.:

Cov.:

AF XY:

0.310

AC XY:

171845

AN XY:

553670

show subpopulations

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

African (AFR)

AF:

0.242

AC:

6349

AN:

26200

American (AMR)

AF:

0.288

AC:

8056

AN:

27928

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

6303

AN:

20612

East Asian (EAS)

AF:

0.313

AC:

9899

AN:

31668

South Asian (SAS)

AF:

0.293

AC:

18084

AN:

61792

European-Finnish (FIN)

AF:

0.302

AC:

10757

AN:

35632

Middle Eastern (MID)

AF:

0.267

AC:

985

AN:

3696

European-Non Finnish (NFE)

AF:

0.316

AC:

271997

AN:

861958

Other (OTH)

AF:

0.307

AC:

14507

AN:

47322

⚠️ 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: 0.283

Heterozygous variant carriers

29306

58611

87917

117222

146528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

10482

20964

31446

41928

52410

<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:

0.0472

AC:

5266

AN:

111628

Hom.:

240

Cov.:

AF XY:

0.0482

AC XY:

2551

AN XY:

52924

show subpopulations

African (AFR)

AF:

0.129

AC:

4347

AN:

33792

American (AMR)

AF:

0.0275

AC:

288

AN:

10476

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

2612

East Asian (EAS)

AF:

0.0212

AC:

AN:

3864

South Asian (SAS)

AF:

0.00460

AC:

AN:

3482

European-Finnish (FIN)

AF:

0.0214

AC:

110

AN:

5132

Middle Eastern (MID)

AF:

0.0248

AC:

AN:

202

European-Non Finnish (NFE)

AF:

0.00737

AC:

367

AN:

49820

Other (OTH)

AF:

0.0294

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

197

395

592

790

987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.108

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=99/1

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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7-82066526-TAAAAAAA-TAAAAAA

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