rs1555515558

Variant names:

• chr16-28887703-TGTGGCTGCCAT-ACGGCATA
• rs1555515558
• NM_004320.6:c.909_920delTGTGGCTGCCATinsACGGCATA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004320.6(ATP2A1):​c.909_920delTGTGGCTGCCATinsACGGCATA​(p.Val304ArgfsTer29) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 16-28887703-TGTGGCTGCCAT-ACGGCATA is Pathogenic according to our data. Variant chr16-28887703-TGTGGCTGCCAT-ACGGCATA is described in ClinVar as Pathogenic. ClinVar VariationId is 464091.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.909_920delTGTGGCTGCCATinsACGGCATA	p.Val304ArgfsTer29	frameshift missense	Exon 8 of 23	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.909_920delTGTGGCTGCCATinsACGGCATA	p.Val304ArgfsTer29	frameshift missense	Exon 8 of 22	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.534_545delTGTGGCTGCCATinsACGGCATA	p.Val179ArgfsTer29	frameshift missense	Exon 6 of 21	NP_001273004.1	O14983-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.909_920delTGTGGCTGCCATinsACGGCATA	p.Val304ArgfsTer29	frameshift missense	Exon 8 of 23	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.909_920delTGTGGCTGCCATinsACGGCATA	p.Val304ArgfsTer29	frameshift missense	Exon 8 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.909_920delTGTGGCTGCCATinsACGGCATA	p.Val304ArgfsTer29	frameshift missense	Exon 8 of 22	ENSP00000349595.3	O14983-1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Brody myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs1555515558; hg19: chr16-28899024;