13-25469029-GGC-G
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_016529.6(ATP8A2):c.130_131del(p.Ala44HisfsTer46) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000242 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
ATP8A2
NM_016529.6 frameshift
NM_016529.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.12
Genes affected
ATP8A2 (HGNC:13533): (ATPase phospholipid transporting 8A2) The protein encoded by this gene is a member of the P4 ATPase family of proteins, which are thought to be involved in a process called lipid flipping, whereby phospholipids are translocated inwards from the exoplasmic leaflet to the cytosolic leaflet of the cell membrane, which aids in generating and maintaining asymmetry in membrane lipids. This protein is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities. In addition, a translocation breakpoint within this gene was observed in an individual with neurological dysfunction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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 13-25469029-GGC-G is Pathogenic according to our data. Variant chr13-25469029-GGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1702569.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP8A2 | NM_016529.6 | c.130_131del | p.Ala44HisfsTer46 | frameshift_variant | 2/37 | ENST00000381655.7 | NP_057613.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP8A2 | ENST00000381655.7 | c.130_131del | p.Ala44HisfsTer46 | frameshift_variant | 2/37 | 1 | NM_016529.6 | ENSP00000371070 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249410Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135364
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GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461748Hom.: 0 AF XY: 0.0000248 AC XY: 18AN XY: 727178
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GnomAD4 genome 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2022 | This variant has not been reported in the literature in individuals affected with ATP8A2-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs774959381, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ala44Hisfs*46) in the ATP8A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP8A2 are known to be pathogenic (PMID: 28454995, 29531481). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at