Genetic Variant NM_018398.3:c.2247-3A>G (chr3-54896746-A-G) – 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.2247-3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,613,662 control chromosomes in the GnomAD database, including 10,957 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1148 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9809 hom. )

Consequence

CACNA2D3
NM_018398.3 splice_region, intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.95

Publications

15 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 = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D3	NM_018398.3 link	c.2247-3A>G		splice_region_variant, intron_variant	Intron 25 of 37	ENST00000474759.6	NP_060868.2	Q8IZS8-1
CACNA2D3-AS1	NR_046666.1 link	n.310T>C		non_coding_transcript_exon_variant	Exon 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6 link	c.2247-3A>G		splice_region_variant, intron_variant	Intron 25 of 37	1	NM_018398.3	ENSP00000419101.1		Q8IZS8-1

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17544

AN:

152020

Hom.:

1146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0750

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.0527

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.0907

AC:

22609

AN:

249272

AF XY:

0.0899

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.0437

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.00851

Gnomad FIN exome

AF:

0.134

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.0961

GnomAD4 exome

AF:

0.111

AC:

161708

AN:

1461524

Hom.:

9809

Cov.:

AF XY:

0.109

AC XY:

79040

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.151

AC:

5045

AN:

33472

American (AMR)

AF:

0.0473

AC:

2117

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

848

AN:

26136

East Asian (EAS)

AF:

0.0132

AC:

524

AN:

39700

South Asian (SAS)

AF:

0.0615

AC:

5309

AN:

86258

European-Finnish (FIN)

AF:

0.131

AC:

6983

AN:

53402

Middle Eastern (MID)

AF:

0.0785

AC:

453

AN:

5768

European-Non Finnish (NFE)

AF:

0.121

AC:

134091

AN:

1111696

Other (OTH)

AF:

0.105

AC:

6338

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

7443

14886

22330

29773

37216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4834

9668

14502

19336

24170

<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:

0.115

AC:

17553

AN:

152138

Hom.:

1148

Cov.:

AF XY:

0.113

AC XY:

8398

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.153

AC:

6350

AN:

41508

American (AMR)

AF:

0.0748

AC:

1144

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

122

AN:

3470

East Asian (EAS)

AF:

0.0110

AC:

AN:

5164

South Asian (SAS)

AF:

0.0529

AC:

255

AN:

4820

European-Finnish (FIN)

AF:

0.132

AC:

1397

AN:

10576

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7971

AN:

67986

Other (OTH)

AF:

0.0992

AC:

210

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

768

1537

2305

3074

3842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.107

Hom.:

831

Bravo

AF:

0.111

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.7

(source)

DANN

Benign

0.63

PhyloP100

2.0

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: 3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over