rs1421005631

Positions:

chr16-28898426-ACT-A

Variant summary

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

The NM_004320.6(ATP2A1):c.1742_1743del(p.Ser581CysfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ATP2A1
NM_004320.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.12

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 16-28898426-ACT-A is Pathogenic according to our data. Variant chr16-28898426-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 446878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATP2A1	NM_004320.6 linkuse as main transcript	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_001286075.2 linkuse as main transcript	c.1367_1368del	p.Ser456CysfsTer7	frameshift_variant	12/21		NP_001273004.1
ATP2A1	NM_173201.5 linkuse as main transcript	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/22		NP_775293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9 linkuse as main transcript	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/23	1	NM_004320.6	ENSP00000378879	P4	O14983-2
ATP2A1	ENST00000357084.7 linkuse as main transcript	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/22	2		ENSP00000349595	A1	O14983-1
ATP2A1	ENST00000536376.5 linkuse as main transcript	c.1367_1368del	p.Ser456CysfsTer7	frameshift_variant	12/21	2		ENSP00000443101		O14983-3
ATP2A1	ENST00000564732.1 linkuse as main transcript	c.385_386del		3_prime_UTR_variant, NMD_transcript_variant	6/7	5		ENSP00000457357

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461762

Hom.:

AF XY:

0.00000688

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	The c.1742_1743delCT variant in the ATP2A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1742_1743delCT variant causes a frameshift starting with codon Serine 581, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Ser581CysfsX7. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1742_1743delCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1742_1743delCT as a pathogenic variant. -

Brody myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 06, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 26248958). This variant has been reported in an individual affected with Brody disease (PMID: 26248958). ClinVar contains an entry for this variant (Variation ID: 446878). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser581Cysfs*7) in the ATP2A1 gene. It is expected to result in an absent or disrupted protein product. -

ATP2A1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2023

The ATP2A1 c.1742_1743delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser581Cysfs*7). This variant was reported in the compound heterozygous state with a canonical splice variant in an individual with Brody myopathy (Mussini et al. 2015. PubMed ID: 26248958; Molenaar et al. 2020. PubMed ID: 32040565). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. 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