rs1555515558

chr16-28887702-CTGTGGCTGCCAT-CACGGCATA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_004320.6(ATP2A1):c.909_920delinsACGGCATA(p.Val304ArgfsTer29) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A1 NM_004320.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-28887703-TGTGGCTGCCAT-ACGGCATA is Pathogenic according to our data. Variant chr16-28887703-TGTGGCTGCCAT-ACGGCATA is described in ClinVar as [Pathogenic]. Clinvar id is 464091.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A1	NM_004320.6	c.909_920delinsACGGCATA	p.Val304ArgfsTer29	frameshift_variant	8/23	ENST00000395503.9
ATP2A1	NM_001286075.2	c.534_545delinsACGGCATA	p.Val179ArgfsTer29	frameshift_variant	6/21
ATP2A1	NM_173201.5	c.909_920delinsACGGCATA	p.Val304ArgfsTer29	frameshift_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.909_920delinsACGGCATA	p.Val304ArgfsTer29	frameshift_variant	8/23	1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.909_920delinsACGGCATA	p.Val304ArgfsTer29	frameshift_variant	8/22	2		A1
ATP2A1	ENST00000536376.5	c.534_545delinsACGGCATA	p.Val179ArgfsTer29	frameshift_variant	6/21	2
ATP2A1	ENST00000564732.1	c.41_52delinsACGGCATA	p.Val15ArgfsTer29	frameshift_variant, NMD_transcript_variant	1/7	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2021

This sequence change creates a premature translational stop signal (p.Val304Argfs*29) in the ATP2A1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP2A1-related disease. Loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 8841193). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555515558; hg19: chr16-28899024;