rs9895012

Positions:

chr17-3941051-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005173.4(ATP2A3):c.2020C>T(p.Arg674Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,613,620 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 59 hom., cov: 33)

Exomes 𝑓: 0.024 ( 531 hom. )

Consequence

ATP2A3
NM_005173.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

ATP2A3 (HGNC:813): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ATP2A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00756824).

BP6

Variant 17-3941051-G-A is Benign according to our data. Variant chr17-3941051-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0217 (3302/152266) while in subpopulation NFE AF= 0.0284 (1932/68012). AF 95% confidence interval is 0.0274. There are 59 homozygotes in gnomad4. There are 1691 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 59 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A3	NM_005173.4 linkuse as main transcript	c.2020C>T	p.Arg674Cys	missense_variant	14/21	ENST00000397041.8	NP_005164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A3	ENST00000397041.8 linkuse as main transcript	c.2020C>T	p.Arg674Cys	missense_variant	14/21	1	NM_005173.4	ENSP00000380234	P1	Q93084-2

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3302

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0645

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0284

Gnomad OTH

AF:

0.0216

GnomAD3 exomes

AF:

0.0226

AC:

5610

AN:

248390

Hom.:

AF XY:

0.0224

AC XY:

3010

AN XY:

134604

show subpopulations

Gnomad AFR exome

AF:

0.00414

Gnomad AMR exome

AF:

0.0167

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.0000553

Gnomad SAS exome

AF:

0.00386

Gnomad FIN exome

AF:

0.0633

Gnomad NFE exome

AF:

0.0276

Gnomad OTH exome

AF:

0.0255

GnomAD4 exome

AF:

0.0244

AC:

35670

AN:

1461354

Hom.:

531

Cov.:

AF XY:

0.0240

AC XY:

17483

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00400

Gnomad4 AMR exome

AF:

0.0174

Gnomad4 ASJ exome

AF:

0.0247

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00399

Gnomad4 FIN exome

AF:

0.0618

Gnomad4 NFE exome

AF:

0.0261

Gnomad4 OTH exome

AF:

0.0207

GnomAD4 genome

AF:

0.0217

AC:

3302

AN:

152266

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1691

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00476

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.0645

Gnomad4 NFE

AF:

0.0284

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0256

Hom.:

Bravo

AF:

0.0175

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0256

AC:

220

ExAC

AF:

0.0210

AC:

2541

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0288

EpiControl

AF:

0.0295

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 243/12994=1.8% -

ATP2A3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.69

.;.;.;.;D;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.86

D;D;.;D;D;D

MetaRNN

Benign

0.0076

T;T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.7

L;L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.25

PROVEAN

Pathogenic

-5.1

D;D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Benign

0.34

T;T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T;T

Polyphen

0.0020

B;B;B;.;B;B

Vest4

0.39

MPC

0.74

ClinPred

0.038

GERP RS

-4.6

Varity_R

0.15

gMVP

0.78

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