Genetic Variant CACNA2D1:c.1516-11_1516-10dupTT (chr7-82005506-G-GAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000722.4(CACNA2D1):c.1516-11_1516-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,199,630 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

CACNA2D1
NM_000722.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.1516-11_1516-10dupTT		intron_variant	Intron 17 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 link	c.1516-10_1516-9insTT		intron_variant	Intron 17 of 38	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes

AF:

0.000251

AC:

AN:

91630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000806

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000626

AC:

AN:

100676

AF XY:

0.000540

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.000591

Gnomad EAS exome

AF:

0.000430

Gnomad FIN exome

AF:

0.0000852

Gnomad NFE exome

AF:

0.000515

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000511

AC:

566

AN:

1107950

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

277

AN XY:

556836

show subpopulations

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

African (AFR)

AF:

0.00193

AC:

AN:

25428

American (AMR)

AF:

0.000505

AC:

AN:

31664

Ashkenazi Jewish (ASJ)

AF:

0.000227

AC:

AN:

22000

East Asian (EAS)

AF:

0.000117

AC:

AN:

34282

South Asian (SAS)

AF:

0.000361

AC:

AN:

69238

European-Finnish (FIN)

AF:

0.0000424

AC:

AN:

47162

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

4078

European-Non Finnish (NFE)

AF:

0.000538

AC:

445

AN:

826796

Other (OTH)

AF:

0.000317

AC:

AN:

47302

⚠️ 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: 0.258

Heterozygous variant carriers

158

236

315

394

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:

0.000251

AC:

AN:

91680

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

AN XY:

44238

show subpopulations

African (AFR)

AF:

0.000803

AC:

AN:

26140

American (AMR)

AF:

0.000222

AC:

AN:

9014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2038

East Asian (EAS)

AF:

0.00

AC:

AN:

2960

South Asian (SAS)

AF:

0.00

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5886

Middle Eastern (MID)

AF:

0.00

AC:

AN:

148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

41010

Other (OTH)

AF:

0.00

AC:

AN:

1222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000281

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Splicing

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

Publications

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7-82005506-GAAAAA-GAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over