16-28902318-GC-GCC

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004320.6(ATP2A1):c.2464dupC(p.Arg822ProfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

ATP2A1
NM_004320.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.140

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-28902318-G-GC is Pathogenic according to our data. Variant chr16-28902318-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6 link	c.2464dupC	p.Arg822ProfsTer39	frameshift_variant	Exon 17 of 23	ENST00000395503.9	NP_004311.1	O14983-2Q7Z675
ATP2A1	NM_173201.5 link	c.2464dupC	p.Arg822ProfsTer39	frameshift_variant	Exon 17 of 22		NP_775293.1	O14983-1Q7Z675
ATP2A1	NM_001286075.2 link	c.2089dupC	p.Arg697ProfsTer39	frameshift_variant	Exon 15 of 21		NP_001273004.1	O14983-3Q7Z675

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP2A1	ENST00000395503.9 link	c.2464dupC	p.Arg822ProfsTer39	frameshift_variant	Exon 17 of 23	1	NM_004320.6	ENSP00000378879.5	O14983-2
ATP2A1	ENST00000357084.7 link	c.2464dupC	p.Arg822ProfsTer39	frameshift_variant	Exon 17 of 22	2		ENSP00000349595.3	O14983-1
ATP2A1	ENST00000536376.5 link	c.2089dupC	p.Arg697ProfsTer39	frameshift_variant	Exon 15 of 21	2		ENSP00000443101.1	O14983-3

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1460506

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

726506

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00252

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000132

AC:

AN:

151532

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

AN XY:

73954

show subpopulations

Gnomad4 AFR

AF:

0.000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brody myopathy

Pathogenic:4Other:1

Dec 03, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg822Profs*39) in the ATP2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 8841193, 10914677, 23911890). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Brody myopathy (PMID: 32040565). ClinVar contains an entry for this variant (Variation ID: 464085). For these reasons, this variant has been classified as Pathogenic. -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP2A1 c.2464dupC (p.Arg822ProfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00035 in 248542 control chromosomes with sufficient coverage in the version 4 of the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATP2A1 causing Brody Myopathy, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2464dupC in individuals affected with Brody Myopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 464085). Based on the evidence outlined above, the variant was classified as pathogenic. -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 12-16-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Pathogenic:2

Nov 29, 2018

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is uninformative because it is below the disease allele frequency. -

Feb 08, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 32528171, 31980526, 32040565) -

ATP2A1-related disorder

Pathogenic:1

Nov 16, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP2A1 c.2464dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg822Profs*39). This variant has been reported in the compound heterozygous state in multiple individuals with Brody myopathy (Molenaar et al. 2020. PubMed ID: 32040565). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-28913639-G-GC). Frameshift variants in ATP2A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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