rs113803159

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_004320.6(ATP2A1):c.663C>G(p.Gly221Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 1,614,078 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0059 ( 32 hom. )

Consequence

ATP2A1
NM_004320.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.0840

Publications

0 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 16-28887457-C-G is Benign according to our data. Variant chr16-28887457-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96544.

BP7

Synonymous conserved (PhyloP=-0.084 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0045 (685/152228) while in subpopulation NFE AF = 0.0075 (510/67994). AF 95% confidence interval is 0.00696. There are 1 homozygotes in GnomAd4. There are 324 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 32 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6 link	c.663C>G	p.Gly221Gly	synonymous_variant	Exon 8 of 23	ENST00000395503.9	NP_004311.1	O14983-2Q7Z675
ATP2A1	NM_173201.5 link	c.663C>G	p.Gly221Gly	synonymous_variant	Exon 8 of 22		NP_775293.1	O14983-1Q7Z675
ATP2A1	NM_001286075.2 link	c.288C>G	p.Gly96Gly	synonymous_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.663C>G	p.Gly221Gly	synonymous_variant	Exon 8 of 23	1	NM_004320.6	ENSP00000378879.5	O14983-2
ATP2A1	ENST00000357084.7 link	c.663C>G	p.Gly221Gly	synonymous_variant	Exon 8 of 22	2		ENSP00000349595.3	O14983-1
ATP2A1	ENST00000536376.5 link	c.288C>G	p.Gly96Gly	synonymous_variant	Exon 6 of 21	2		ENSP00000443101.1	O14983-3
ATP2A1	ENST00000564732.1 link	n.-208C>G		upstream_gene_variant		5		ENSP00000457357.1	H3BTW4

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00750

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00459

AC:

1150

AN:

250754

AF XY:

0.00468

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00552

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00736

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00585

AC:

8555

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

4198

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.00503

AC:

225

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000452

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00395

AC:

211

AN:

53382

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00700

AC:

7784

AN:

1112010

Other (OTH)

AF:

0.00407

AC:

246

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

530

1060

1589

2119

2649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.00450

AC:

685

AN:

152228

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

324

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41542

American (AMR)

AF:

0.00504

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00750

AC:

510

AN:

67994

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00591

Hom.:

Bravo

AF:

0.00450

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00776

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Feb 26, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATP2A1: BP4, BP7, BS2 -

Sep 29, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brody myopathy

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

May 03, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATP2A1-related disorder

Benign:1

May 29, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

4.9

(source)

DANN

Benign

0.68

PhyloP100

-0.084

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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