rs121912737
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The ENST00000539276.7(ATP2A2):c.1805C>T(p.Pro602Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P602A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000539276.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP2A2 | NM_170665.4 | c.1805C>T | p.Pro602Leu | missense_variant | 14/20 | ENST00000539276.7 | NP_733765.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP2A2 | ENST00000539276.7 | c.1805C>T | p.Pro602Leu | missense_variant | 14/20 | 1 | NM_170665.4 | ENSP00000440045 | P3 | |
ATP2A2 | ENST00000308664.10 | c.1805C>T | p.Pro602Leu | missense_variant | 14/21 | 1 | ENSP00000311186 | A1 | ||
ATP2A2 | ENST00000548169.2 | c.1478C>T | p.Pro493Leu | missense_variant | 10/16 | 2 | ENSP00000449454 | |||
ATP2A2 | ENST00000377685.9 | c.*1645C>T | 3_prime_UTR_variant, NMD_transcript_variant | 13/20 | 5 | ENSP00000366913 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2021 | Published functional studies demonstrate a damaging effect: undetectable ATPase activity and impaired Ca2+ binding and transport (Dhitavat et al., 2003; Dode et al., 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12975374, 22814319, 28035777, 28498512, 25622760, 12542527, 16716163) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP2A2 function (PMID: 12542527). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP2A2 protein function. ClinVar contains an entry for this variant (Variation ID: 17799). This missense change has been observed in individuals with acrokeratosis verruciformis of Hopf (PMID: 12542527, 22814319, 25622760, 28035777, 28498512). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 602 of the ATP2A2 protein (p.Pro602Leu). - |
Acrokeratosis verruciformis of Hopf Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at