rs9895012

Variant names:

• chr17-3941051-G-A
• rs9895012
• NM_005173.4:c.2020C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.33
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A3	NM_005173.4	c.2020C>T	p.Arg674Cys	missense_variant	Exon 14 of 21	ENST00000397041.8	NP_005164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A3	ENST00000397041.8	c.2020C>T	p.Arg674Cys	missense_variant	Exon 14 of 21	1	NM_005173.4	ENSP00000380234.3

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

GnomAD2 exomes AF: 0.0226 AC: 5610 AN: 248390 AF XY: 0.0224

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 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

African (AFR) AF: 0.00400 AC: 134 AN: 33466

American (AMR) AF: 0.0174 AC: 777 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 644 AN: 26096

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39686

South Asian (SAS) AF: 0.00399 AC: 344 AN: 86222

European-Finnish (FIN) AF: 0.0618 AC: 3298 AN: 53360

Middle Eastern (MID) AF: 0.0319 AC: 184 AN: 5766

European-Non Finnish (NFE) AF: 0.0261 AC: 29036 AN: 1111698

Other (OTH) AF: 0.0207 AC: 1248 AN: 60358

GnomAD4 genome AF: 0.0217 AC: 3302 AN: 152266 Hom.: 59 Cov.: 33 AF XY: 0.0227 AC XY: 1691 AN XY: 74428

African (AFR) AF: 0.00476 AC: 198 AN: 41570

American (AMR) AF: 0.0214 AC: 327 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.0645 AC: 685 AN: 10612

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0284 AC: 1932 AN: 68012

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.0240 Hom.: 49

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: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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
DEOGEN2	Benign	0.0	.;.;.;.;D;.
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
PhyloP100		1.3
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
Vest4		0.39
ClinPred		0.038	T
GERP RS		-4.6
Varity_R		0.15
gMVP		0.78
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9895012; hg19: chr17-3844345;