Genetic Variant NM_000722.4:c.3160-9delT (chr7-81950516-TA-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_000722.4(CACNA2D1):c.3160-9delT variant causes a intron change. The variant allele was found at a frequency of 0.00148 in 1,413,882 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

CACNA2D1
NM_000722.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 4.16

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
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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 7-81950516-TA-T is Benign according to our data. Variant chr7-81950516-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1165755.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Unknown,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.3160-9delT		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.3196-9delT		intron	N/A	NP_001353796.1	P54289-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.3160-9delT	intron	N/A	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000443883.2	TSL:5	c.3196-9delT	intron	N/A	ENSP00000409374.2	H0Y715
CACNA2D1	ENST00000957014.1		c.3181-9delT	intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes

AF:

0.000278

AC:

AN:

147472

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000996

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000680

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00395

Gnomad SAS

AF:

0.000643

Gnomad FIN

AF:

0.000728

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000900

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00956

AC:

1531

AN:

160184

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.00521

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.00800

Gnomad EAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.00540

Gnomad NFE exome

AF:

0.00857

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.00162

AC:

2054

AN:

1266320

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1143

AN XY:

629472

show subpopulations

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

African (AFR)

AF:

0.00280

AC:

AN:

28246

American (AMR)

AF:

0.00801

AC:

287

AN:

35842

Ashkenazi Jewish (ASJ)

AF:

0.00280

AC:

AN:

21396

East Asian (EAS)

AF:

0.00355

AC:

116

AN:

32704

South Asian (SAS)

AF:

0.00537

AC:

378

AN:

70404

European-Finnish (FIN)

AF:

0.00284

AC:

129

AN:

45398

Middle Eastern (MID)

AF:

0.00238

AC:

AN:

5044

European-Non Finnish (NFE)

AF:

0.000888

AC:

867

AN:

976026

Other (OTH)

AF:

0.00246

AC:

126

AN:

51260

⚠️ 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: 0.271

Heterozygous variant carriers

287

574

860

1147

1434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000271

AC:

AN:

147562

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

AN XY:

71816

show subpopulations

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

African (AFR)

AF:

0.0000994

AC:

AN:

40250

American (AMR)

AF:

0.0000680

AC:

AN:

14712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.00377

AC:

AN:

5046

South Asian (SAS)

AF:

0.000644

AC:

AN:

4658

European-Finnish (FIN)

AF:

0.000728

AC:

AN:

9614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000900

AC:

AN:

66692

Other (OTH)

AF:

0.00

AC:

AN:

2008

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000109624), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.376

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:

0.0196

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brugada syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=100/0

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

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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