3-54581847-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_018398.3(CACNA2D3):c.933T>G(p.Thr311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,780 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0039 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 54 hom. )

Consequence

CACNA2D3
NM_018398.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.11

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 3-54581847-T-G is Benign according to our data. Variant chr3-54581847-T-G is described in ClinVar as [Benign]. Clinvar id is 3049724.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-4.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00333 (4866/1461518) while in subpopulation AMR AF= 0.0354 (1581/44678). AF 95% confidence interval is 0.0339. There are 54 homozygotes in gnomad4_exome. There are 2361 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D3	NM_018398.3 linkuse as main transcript	c.933T>G	p.Thr311=	synonymous_variant	9/38	ENST00000474759.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D3	ENST00000474759.6 linkuse as main transcript	c.933T>G	p.Thr311=	synonymous_variant	9/38	1	NM_018398.3	P1	Q8IZS8-1

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.0147

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00830

AC:

2064

AN:

248730

Hom.:

AF XY:

0.00703

AC XY:

948

AN XY:

134930

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.0382

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00589

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.00194

Gnomad OTH exome

AF:

0.00581

GnomAD4 exome

AF:

0.00333

AC:

4866

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

2361

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0354

Gnomad4 ASJ exome

AF:

0.00291

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00607

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.00159

Gnomad4 OTH exome

AF:

0.00315

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152262

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.0163

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.0147

Gnomad4 NFE

AF:

0.00166

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.00488

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CACNA2D3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2021

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

BayesDel_noAF

Benign

-0.93

Cadd

Benign

0.027

Dann

Benign

0.57

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