Genetic Variant CACNA2D1:c.1516-11_1516-10delTT (chr7-82005506-GAA-G) – 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_1516-10delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,174,770 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 0.000065 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0040 ( 0 hom. )

Consequence

CACNA2D1
NM_000722.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.342

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_1516-10delTT		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.1516-11_1516-10delTT		intron_variant	Intron 17 of 38	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes

AF:

0.0000655

AC:

AN:

91606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000732

Gnomad OTH

AF:

0.000824

GnomAD2 exomes

AF:

0.00374

AC:

377

AN:

100676

AF XY:

0.00356

show subpopulations

Gnomad AFR exome

AF:

0.00446

Gnomad AMR exome

AF:

0.00441

Gnomad ASJ exome

AF:

0.00256

Gnomad EAS exome

AF:

0.00401

Gnomad FIN exome

AF:

0.00239

Gnomad NFE exome

AF:

0.00439

Gnomad OTH exome

AF:

0.00352

GnomAD4 exome

AF:

0.00397

AC:

4295

AN:

1083116

Hom.:

AF XY:

0.00364

AC XY:

1983

AN XY:

544926

show subpopulations

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

African (AFR)

AF:

0.00385

AC:

AN:

24964

American (AMR)

AF:

0.00319

AC:

AN:

31056

Ashkenazi Jewish (ASJ)

AF:

0.00200

AC:

AN:

21544

East Asian (EAS)

AF:

0.00164

AC:

AN:

33540

South Asian (SAS)

AF:

0.00188

AC:

128

AN:

68168

European-Finnish (FIN)

AF:

0.00108

AC:

AN:

46348

Middle Eastern (MID)

AF:

0.00101

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.00454

AC:

3662

AN:

807278

Other (OTH)

AF:

0.00342

AC:

158

AN:

46242

⚠️ 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: 0.255

Heterozygous variant carriers

566

1132

1699

2265

2831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

186

372

558

744

930

<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:

0.0000655

AC:

AN:

91654

Hom.:

Cov.:

AF XY:

0.0000905

AC XY:

AN XY:

44222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26140

American (AMR)

AF:

0.00

AC:

AN:

9012

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:

0.000340

AC:

AN:

5874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

148

European-Non Finnish (NFE)

AF:

0.0000732

AC:

AN:

40998

Other (OTH)

AF:

0.000818

AC:

AN:

1222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

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:

0.00258

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.34

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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7-82005506-GAAAAA-GAAA

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