rs143777158

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004320.6(ATP2A1):c.839A>G(p.Asn280Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 1,614,074 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. N280K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 12 hom. )

Consequence

ATP2A1
NM_004320.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.24

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Brody myopathy
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ATP2A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013020366).

BP6

Variant 16-28887633-A-G is Benign according to our data. Variant chr16-28887633-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 387826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00381 (580/152196) while in subpopulation AFR AF = 0.013 (541/41534). AF 95% confidence interval is 0.0121. There are 4 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 8 of 23	ENST00000395503.9	NP_004311.1	O14983-2Q7Z675
ATP2A1	NM_173201.5 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 8 of 22		NP_775293.1	O14983-1Q7Z675
ATP2A1	NM_001286075.2 link	c.464A>G	p.Asn155Ser	missense_variant	Exon 6 of 21		NP_001273004.1	O14983-3Q7Z675

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP2A1	ENST00000395503.9 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 8 of 23	1	NM_004320.6	ENSP00000378879.5	O14983-2
ATP2A1	ENST00000357084.7 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 8 of 22	2		ENSP00000349595.3	O14983-1
ATP2A1	ENST00000536376.5 link	c.464A>G	p.Asn155Ser	missense_variant	Exon 6 of 21	2		ENSP00000443101.1	O14983-3
ATP2A1	ENST00000564732.1 link	n.-32A>G		upstream_gene_variant		5		ENSP00000457357.1	H3BTW4

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

577

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000951

AC:

239

AN:

251278

AF XY:

0.000692

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000507

AC:

741

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

342

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0152

AC:

509

AN:

33480

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1112010

Other (OTH)

AF:

0.00156

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00381

AC:

580

AN:

152196

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

275

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0130

AC:

541

AN:

41534

American (AMR)

AF:

0.00124

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67994

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00435

ESP6500AA

AF:

0.0100

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brody myopathy

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 13, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.70

D;.;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.41

N;N;.

PhyloP100

3.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.75

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.18

MVP

0.96

MPC

1.1

ClinPred

0.018

GERP RS

4.3

Varity_R

0.18

gMVP

0.67

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over