3-54899845-A-G

Position:

chr3-54899845-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_018398.3(CACNA2D3):c.2426A>G(p.Glu809Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 1,605,322 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 50 hom. )

Consequence

CACNA2D3
NM_018398.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 8.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008630425).

BP6

Variant 3-54899845-A-G is Benign according to our data. Variant chr3-54899845-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3038777.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D3	NM_018398.3 linkuse as main transcript	c.2426A>G	p.Glu809Gly	missense_variant	27/38	ENST00000474759.6
CACNA2D3-AS1	NR_046666.1 linkuse as main transcript	n.97+1314T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D3	ENST00000474759.6 linkuse as main transcript	c.2426A>G	p.Glu809Gly	missense_variant	27/38	1	NM_018398.3	P1	Q8IZS8-1
CACNA2D3	ENST00000490478.5 linkuse as main transcript	c.2144A>G	p.Glu715Gly	missense_variant	26/37	1			Q8IZS8-2
CACNA2D3	ENST00000471363.5 linkuse as main transcript	c.*504A>G		3_prime_UTR_variant, NMD_transcript_variant	24/35	1			Q8IZS8-3
CACNA2D3-AS1	ENST00000471265.1 linkuse as main transcript	n.97+1314T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00440

AC:

670

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00603

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00377

AC:

887

AN:

235524

Hom.:

AF XY:

0.00393

AC XY:

499

AN XY:

127014

show subpopulations

Gnomad AFR exome

AF:

0.00410

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00282

Gnomad FIN exome

AF:

0.00307

Gnomad NFE exome

AF:

0.00559

Gnomad OTH exome

AF:

0.00486

GnomAD4 exome

AF:

0.00585

AC:

8506

AN:

1452982

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4147

AN XY:

721760

show subpopulations

Gnomad4 AFR exome

AF:

0.00452

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00301

Gnomad4 FIN exome

AF:

0.00327

Gnomad4 NFE exome

AF:

0.00674

Gnomad4 OTH exome

AF:

0.00619

GnomAD4 genome

AF:

0.00440

AC:

670

AN:

152340

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

302

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00435

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00603

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00477

Hom.:

Bravo

AF:

0.00431

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00464

AC:

ESP6500EA

AF:

0.00543

AC:

ExAC

AF:

0.00406

AC:

491

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CACNA2D3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.88

DEOGEN2

Benign

0.042

T;T;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

0.036

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;D;.;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.57

N;N;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.49

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.71

T;T;T;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.27

MVP

0.13

MPC

0.33

ClinPred

0.035

GERP RS

5.6

Varity_R

0.13

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over