Genetic Variant NM_000722.4:c.355-6_355-5dupTT (chr7-82136680-C-CAA) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000722.4(CACNA2D1):c.355-6_355-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,325,098 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 5 hom., cov: 30)

Exomes 𝑓: 0.0032 ( 9 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 -16 ACMG points.

BP6

Variant 7-82136680-C-CAA is Benign according to our data. Variant chr7-82136680-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 220682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00324 (452/139332) while in subpopulation SAS AF = 0.0365 (160/4386). AF 95% confidence interval is 0.0319. There are 5 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.355-6_355-5dupTT		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.355-5_355-4insTT		splice_region_variant, intron_variant	Intron 4 of 38	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

454

AN:

139240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000799

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00537

Gnomad SAS

AF:

0.0363

Gnomad FIN

AF:

0.000121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000142

Gnomad OTH

AF:

0.00211

GnomAD2 exomes

AF:

0.00652

AC:

759

AN:

116500

AF XY:

0.00774

show subpopulations

Gnomad AFR exome

AF:

0.00844

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00758

Gnomad FIN exome

AF:

0.000760

Gnomad NFE exome

AF:

0.000594

Gnomad OTH exome

AF:

0.00313

GnomAD4 exome

AF:

0.00322

AC:

3818

AN:

1185766

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

2270

AN XY:

587558

show subpopulations

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

African (AFR)

AF:

0.00864

AC:

234

AN:

27086

American (AMR)

AF:

0.00272

AC:

AN:

32368

Ashkenazi Jewish (ASJ)

AF:

0.00127

AC:

AN:

20466

East Asian (EAS)

AF:

0.00662

AC:

209

AN:

31568

South Asian (SAS)

AF:

0.0314

AC:

2047

AN:

65202

European-Finnish (FIN)

AF:

0.000528

AC:

AN:

37900

Middle Eastern (MID)

AF:

0.00540

AC:

AN:

4818

European-Non Finnish (NFE)

AF:

0.00110

AC:

1005

AN:

917744

Other (OTH)

AF:

0.00335

AC:

163

AN:

48614

⚠️ 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: 0.331

Heterozygous variant carriers

212

424

637

849

1061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00324

AC:

452

AN:

139332

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

257

AN XY:

67328

show subpopulations

African (AFR)

AF:

0.00630

AC:

241

AN:

38264

American (AMR)

AF:

0.000798

AC:

AN:

13788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3286

East Asian (EAS)

AF:

0.00538

AC:

AN:

4836

South Asian (SAS)

AF:

0.0365

AC:

160

AN:

4386

European-Finnish (FIN)

AF:

0.000121

AC:

AN:

8246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000142

AC:

AN:

63458

Other (OTH)

AF:

0.00209

AC:

AN:

1914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00187

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 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 03, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.021

Mutation Taster

=99/1

polymorphism

(source)

Splicing

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