rs1421005631

chr16-28898426-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.12

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 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	UniProt
ATP2A1	NM_004320.6	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/23	ENST00000395503.9
ATP2A1	NM_001286075.2	c.1367_1368del	p.Ser456CysfsTer7	frameshift_variant	12/21
ATP2A1	NM_173201.5	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/23	1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.1742_1743del	p.Ser581CysfsTer7	frameshift_variant	14/22	2		A1
ATP2A1	ENST00000536376.5	c.1367_1368del	p.Ser456CysfsTer7	frameshift_variant	12/21	2
ATP2A1	ENST00000564732.1	c.*385_*386del		3_prime_UTR_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151808 Hom.: 0 Cov.: 32

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: 16 AN: 1461762 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727182

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: 2 AN: 151808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74160

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

Submissions by phenotype

not provided Pathogenic:2

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2017	- -

Brody myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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

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

Other links and lift over

dbSNP: rs1421005631; hg19: chr16-28909747;