rs121918114
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004320.6(ATP2A1):c.2025C>A(p.Cys675Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000144 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
ATP2A1
NM_004320.6 stop_gained
NM_004320.6 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.51
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]
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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 16-28900841-C-A is Pathogenic according to our data. Variant chr16-28900841-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 17803.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.2025C>A | p.Cys675Ter | stop_gained | 15/23 | ENST00000395503.9 | |
ATP2A1 | NM_173201.5 | c.2025C>A | p.Cys675Ter | stop_gained | 15/22 | ||
ATP2A1 | NM_001286075.2 | c.1650C>A | p.Cys550Ter | stop_gained | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP2A1 | ENST00000395503.9 | c.2025C>A | p.Cys675Ter | stop_gained | 15/23 | 1 | NM_004320.6 | P4 | |
ATP2A1 | ENST00000357084.7 | c.2025C>A | p.Cys675Ter | stop_gained | 15/22 | 2 | A1 | ||
ATP2A1 | ENST00000536376.5 | c.1650C>A | p.Cys550Ter | stop_gained | 13/21 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249188Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134916
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727242
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GnomAD4 genome ? Cov.: 31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brody myopathy Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 01, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change creates a premature translational stop signal (p.Cys675*) in the ATP2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 8841193, 10914677, 23911890). This variant is present in population databases (rs121918114, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Brody myopathy (PMID: 8841193). ClinVar contains an entry for this variant (Variation ID: 17803). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at