rs1421005631

Variant names:

• chr16-28898426-ACT-A
• rs1421005631
• NM_004320.6:c.1742_1743delCT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004320.6(ATP2A1):​c.1742_1743delCT​(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
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-28898426-ACT-A is Pathogenic according to our data. Variant chr16-28898426-ACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 446878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004320.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.1742_1743delCT	p.Ser581CysfsTer7	frameshift	Exon 14 of 23	NP_004311.1
	ATP2A1	NM_173201.5		c.1742_1743delCT	p.Ser581CysfsTer7	frameshift	Exon 14 of 22	NP_775293.1
	ATP2A1	NM_001286075.2		c.1367_1368delCT	p.Ser456CysfsTer7	frameshift	Exon 12 of 21	NP_001273004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1742_1743delCT	p.Ser581CysfsTer7	frameshift	Exon 14 of 23	ENSP00000378879.5
	ATP2A1	ENST00000357084.7	TSL:2	c.1742_1743delCT	p.Ser581CysfsTer7	frameshift	Exon 14 of 22	ENSP00000349595.3
	ATP2A1	ENST00000536376.5	TSL:2	c.1367_1368delCT	p.Ser456CysfsTer7	frameshift	Exon 12 of 21	ENSP00000443101.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74160

African (AFR) AF: 0.00 AC: 0 AN: 41196

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

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

Jan 20, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 19, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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 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

Apr 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1421005631; hg19: chr16-28909747;