3-54891399-C-T

Position:

chr3-54891399-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_018398.3(CACNA2D3):c.2195C>T(p.Thr732Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00967 in 1,613,880 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0076 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 73 hom. )

Consequence

CACNA2D3
NM_018398.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 7.57

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014728785).

BP6

Variant 3-54891399-C-T is Benign according to our data. Variant chr3-54891399-C-T is described in ClinVar as [Benign]. Clinvar id is 773444.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D3	NM_018398.3 linkuse as main transcript	c.2195C>T	p.Thr732Met	missense_variant	25/38	ENST00000474759.6
CACNA2D3-AS1	NR_046666.1 linkuse as main transcript	n.533+3214G>A		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.2195C>T	p.Thr732Met	missense_variant	25/38	1	NM_018398.3	P1	Q8IZS8-1
CACNA2D3	ENST00000490478.5 linkuse as main transcript	c.1913C>T	p.Thr638Met	missense_variant	24/37	1			Q8IZS8-2
CACNA2D3	ENST00000471363.5 linkuse as main transcript	c.*273C>T		3_prime_UTR_variant, NMD_transcript_variant	22/35	1			Q8IZS8-3
CACNA2D3-AS1	ENST00000471265.1 linkuse as main transcript	n.533+3214G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00756

AC:

1150

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00768

AC:

1914

AN:

249180

Hom.:

AF XY:

0.00752

AC XY:

1016

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.00245

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00810

GnomAD4 exome

AF:

0.00989

AC:

14460

AN:

1461628

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

7069

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.00195

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00260

Gnomad4 FIN exome

AF:

0.0214

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00740

GnomAD4 genome

AF:

0.00757

AC:

1152

AN:

152252

Hom.:

Cov.:

AF XY:

0.00779

AC XY:

580

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0262

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00842

Hom.:

Bravo

AF:

0.00574

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00213

AC:

ESP6500EA

AF:

0.0111

AC:

ExAC

AF:

0.00761

AC:

919

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00960

EpiControl

AF:

0.00759

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2018

- -

CACNA2D3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;T;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.89

.;D;.;D

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.94

MVP

0.19

MPC

0.91

ClinPred

0.018

GERP RS

5.5

Varity_R

0.28

gMVP

0.86

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