Genetic Variant CACNA2D3:c.1783-9dupT (chr3-54879327-C-CT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_018398.3(CACNA2D3):c.1783-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.018 ( 67 hom., cov: 0)

Exomes 𝑓: 0.033 ( 2 hom. )

Consequence

CACNA2D3
NM_018398.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

Publications

1 publications found

Variant links:

Genes affected

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

CACNA2D3 links:

CACNA2D3-AS1 (HGNC:40702): (CACNA2D3 antisense RNA 1)

CACNA2D3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018398.3. 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
	CACNA2D3	NM_018398.3	MANE Select	c.1783-9dupT		splice_region intron	N/A	NP_060868.2	Q8IZS8-1
	CACNA2D3-AS1	NR_046666.1		n.534-384dupA		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.1783-23_1783-22insT	intron	N/A	ENSP00000419101.1	Q8IZS8-1
CACNA2D3	ENST00000490478.5	TSL:1	c.1501-23_1501-22insT	intron	N/A	ENSP00000417279.1	Q8IZS8-2
CACNA2D3	ENST00000468658.1	TSL:1	n.1197-23_1197-22insT	intron	N/A	ENSP00000417455.1	F8WAV4

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2579

AN:

143790

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0596

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.00296

Gnomad EAS

AF:

0.000399

Gnomad SAS

AF:

0.00243

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00676

Gnomad NFE

AF:

0.000959

Gnomad OTH

AF:

0.0162

GnomAD2 exomes

AF:

0.0251

AC:

3976

AN:

158340

AF XY:

0.0236

show subpopulations

Gnomad AFR exome

AF:

0.0824

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.00525

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0249

Gnomad OTH exome

AF:

0.0290

GnomAD4 exome

AF:

0.0331

AC:

39910

AN:

1205820

Hom.:

Cov.:

AF XY:

0.0318

AC XY:

19215

AN XY:

603824

show subpopulations

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

African (AFR)

AF:

0.0907

AC:

2423

AN:

26720

American (AMR)

AF:

0.0121

AC:

391

AN:

32192

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

520

AN:

22584

East Asian (EAS)

AF:

0.00260

AC:

AN:

34658

South Asian (SAS)

AF:

0.0238

AC:

1703

AN:

71464

European-Finnish (FIN)

AF:

0.0147

AC:

629

AN:

42810

Middle Eastern (MID)

AF:

0.0288

AC:

137

AN:

4760

European-Non Finnish (NFE)

AF:

0.0353

AC:

32462

AN:

920064

Other (OTH)

AF:

0.0308

AC:

1555

AN:

50568

⚠️ 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: 0.272

Heterozygous variant carriers

4167

8333

12500

16666

20833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1386

2772

4158

5544

6930

<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:

0.0179

AC:

2580

AN:

143828

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1186

AN XY:

69694

show subpopulations

African (AFR)

AF:

0.0595

AC:

2328

AN:

39096

American (AMR)

AF:

0.00831

AC:

121

AN:

14568

Ashkenazi Jewish (ASJ)

AF:

0.00296

AC:

AN:

3376

East Asian (EAS)

AF:

0.000400

AC:

AN:

4996

South Asian (SAS)

AF:

0.00222

AC:

AN:

4502

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

8488

Middle Eastern (MID)

AF:

0.00714

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000960

AC:

AN:

65654

Other (OTH)

AF:

0.0161

AC:

AN:

1986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

113

226

339

452

565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0169

Hom.:

445

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

3-54879327-CTTTTT-CTTTTTT

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