Genetic Variant CACNA2D1:c.3160-10_3160-9dupTT (chr7-81950516-T-TAA) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000722.4(CACNA2D1):c.3160-10_3160-9dupTT variant causes a intron change. The variant allele was found at a frequency of 0.000569 in 1,453,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

CACNA2D1
NM_000722.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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 -2 ACMG points.

BP6

Variant 7-81950516-T-TAA is Benign according to our data. Variant chr7-81950516-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 1166600.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3160-10_3160-9dupTT		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.3196-10_3196-9dupTT		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.3160-9_3160-8insTT	intron	N/A	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000443883.2	TSL:5	c.3196-9_3196-8insTT	intron	N/A	ENSP00000409374.2	H0Y715
CACNA2D1	ENST00000957014.1		c.3181-9_3181-8insTT	intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes

AF:

0.000291

AC:

AN:

147552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000295

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000214

Gnomad FIN

AF:

0.000104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000510

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000574

AC:

AN:

160184

AF XY:

0.000510

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.000797

Gnomad ASJ exome

AF:

0.000327

Gnomad EAS exome

AF:

0.0000905

Gnomad FIN exome

AF:

0.000400

Gnomad NFE exome

AF:

0.000709

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000601

AC:

785

AN:

1305412

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

349

AN XY:

649210

show subpopulations

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

African (AFR)

AF:

0.000341

AC:

AN:

29336

American (AMR)

AF:

0.000533

AC:

AN:

37498

Ashkenazi Jewish (ASJ)

AF:

0.0000447

AC:

AN:

22366

East Asian (EAS)

AF:

0.0000291

AC:

AN:

34356

South Asian (SAS)

AF:

0.000203

AC:

AN:

73980

European-Finnish (FIN)

AF:

0.000466

AC:

AN:

47164

Middle Eastern (MID)

AF:

0.000385

AC:

AN:

5196

European-Non Finnish (NFE)

AF:

0.000698

AC:

700

AN:

1002414

Other (OTH)

AF:

0.000264

AC:

AN:

53102

⚠️ 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: 0.359

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000284

AC:

AN:

147642

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

AN XY:

71852

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

40258

American (AMR)

AF:

0.00

AC:

AN:

14720

Ashkenazi Jewish (ASJ)

AF:

0.000295

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

5050

South Asian (SAS)

AF:

0.000215

AC:

AN:

4660

European-Finnish (FIN)

AF:

0.000104

AC:

AN:

9638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000510

AC:

AN:

66722

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000348

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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7-81950516-TAAAAA-TAAAAAAA

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