Genetic Variant NM_018398.3:c.7G>C (chr3-54122720-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018398.3(CACNA2D3):c.7G>C(p.Gly3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,195,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

CACNA2D3
NM_018398.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.873

Publications

0 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:

ENSG00000286353 (HGNC:):

ENSG00000286353 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0411793).

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.7G>C	p.Gly3Arg	missense	Exon 1 of 38	NP_060868.2	Q8IZS8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.7G>C	p.Gly3Arg	missense	Exon 1 of 38	ENSP00000419101.1	Q8IZS8-1
CACNA2D3	ENST00000958523.1		c.7G>C	p.Gly3Arg	missense	Exon 1 of 37	ENSP00000628582.1
CACNA2D3	ENST00000958525.1		c.7G>C	p.Gly3Arg	missense	Exon 1 of 36	ENSP00000628584.1

Frequencies

GnomAD3 genomes

AF:

0.000180

AC:

AN:

149936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000252

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000412

AC:

431

AN:

1045830

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

203

AN XY:

493490

show subpopulations

African (AFR)

AF:

0.0000465

AC:

AN:

21526

American (AMR)

AF:

0.000419

AC:

AN:

7168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12736

East Asian (EAS)

AF:

0.00

AC:

AN:

23508

South Asian (SAS)

AF:

0.000104

AC:

AN:

19204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2738

European-Non Finnish (NFE)

AF:

0.000464

AC:

416

AN:

897318

Other (OTH)

AF:

0.000220

AC:

AN:

40952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000180

AC:

AN:

150042

Hom.:

Cov.:

AF XY:

0.000218

AC XY:

AN XY:

73314

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

41116

American (AMR)

AF:

0.000132

AC:

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.000416

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000252

AC:

AN:

67354

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000208

Hom.:

Bravo

AF:

0.000185

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.056

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

-0.87

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.30

REVEL

Benign

0.056

Sift

Benign

0.52

Sift4G

Benign

0.082

Polyphen

0.0

Vest4

0.10

MutPred

0.24

Gain of MoRF binding (P = 0.0122)

MVP

0.043

MPC

0.31

ClinPred

0.20

GERP RS

-2.9

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.047

gMVP

0.32

Mutation Taster

=92/8

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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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