rs9895012

chr17-3941051-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R674H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.022 (59 hom., cov: 33)
  • Exomes 𝑓: 0.024 (531 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 59 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.2020C>T	p.Arg674Cys	missense_variant	14/21	ENST00000397041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A3	ENST00000397041.8	c.2020C>T	p.Arg674Cys	missense_variant	14/21	1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3302 AN: 152148 Hom.: 59 Cov.: 33

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.: 92 AF XY: 0.0224 AC XY: 3010 AN XY: 134604

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.: 33 AF XY: 0.0240 AC XY: 17483 AN XY: 726986

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.: 59 Cov.: 33 AF XY: 0.0227 AC XY: 1691 AN XY: 74428

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.: 40

Bravo AF: 0.0175

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0256 AC: 220

ExAC AF: 0.0210 AC: 2541

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0295

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 condition Benign:1

Benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	17
Dann	Benign	0.93
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D;D;.;D;D;D
MetaRNN	Benign	0.0076	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
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	T
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	T
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

Other links and lift over

dbSNP: rs9895012; hg19: chr17-3844345;