rs200092983

Positions:

chr16-28898248-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000395503.9(ATP2A1):c.1561G>A(p.Val521Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

ATP2A1
ENST00000395503.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

ATP2A1 (HGNC:811): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1) 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 muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

ATP2A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATP2A1	NM_004320.6 linkuse as main transcript	c.1561G>A	p.Val521Ile	missense_variant	14/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5 linkuse as main transcript	c.1561G>A	p.Val521Ile	missense_variant	14/22		NP_775293.1
ATP2A1	NM_001286075.2 linkuse as main transcript	c.1186G>A	p.Val396Ile	missense_variant	12/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9 linkuse as main transcript	c.1561G>A	p.Val521Ile	missense_variant	14/23	1	NM_004320.6	ENSP00000378879	P4	O14983-2
ATP2A1	ENST00000357084.7 linkuse as main transcript	c.1561G>A	p.Val521Ile	missense_variant	14/22	2		ENSP00000349595	A1	O14983-1
ATP2A1	ENST00000536376.5 linkuse as main transcript	c.1186G>A	p.Val396Ile	missense_variant	12/21	2		ENSP00000443101		O14983-3
ATP2A1	ENST00000564732.1 linkuse as main transcript	c.*204G>A		3_prime_UTR_variant, NMD_transcript_variant	6/7	5		ENSP00000457357

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251420

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000199

AC:

291

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000105

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brody myopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 521 of the ATP2A1 protein (p.Val521Ile). This variant is present in population databases (rs200092983, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423726). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.1561G>A (p.V521I) alteration is located in exon 14 (coding exon 14) of the ATP2A1 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the valine (V) at amino acid position 521 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2017

A variant of uncertain significance has been identified in the ATP2A1 gene. The V521I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V521I variant is observed in 2/8646 (0.02%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V521I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

-0.079

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.085

N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.21

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.53

T;T;T

Sift4G

Benign

0.86

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.66

MutPred

0.62

Loss of MoRF binding (P = 0.1413);Loss of MoRF binding (P = 0.1413);.;

MVP

0.63

MPC

0.56

ClinPred

0.069

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.48

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