16-28887236-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004320.6(ATP2A1):c.592C>T(p.Arg198*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,744 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
Consequence
NM_004320.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP2A1 | NM_004320.6 | c.592C>T | p.Arg198* | stop_gained | Exon 7 of 23 | ENST00000395503.9 | NP_004311.1 | |
ATP2A1 | NM_173201.5 | c.592C>T | p.Arg198* | stop_gained | Exon 7 of 22 | NP_775293.1 | ||
ATP2A1 | NM_001286075.2 | c.217C>T | p.Arg73* | stop_gained | Exon 5 of 21 | NP_001273004.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP2A1 | ENST00000395503.9 | c.592C>T | p.Arg198* | stop_gained | Exon 7 of 23 | 1 | NM_004320.6 | ENSP00000378879.5 | ||
ATP2A1 | ENST00000357084.7 | c.592C>T | p.Arg198* | stop_gained | Exon 7 of 22 | 2 | ENSP00000349595.3 | |||
ATP2A1 | ENST00000536376.5 | c.217C>T | p.Arg73* | stop_gained | Exon 5 of 21 | 2 | ENSP00000443101.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151850Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151850Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74136
ClinVar
Submissions by phenotype
Brody myopathy Pathogenic:2
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For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg198*) 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 not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with Brody myopathy (PMID: 8841193). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17802). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at