rs786205056
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_022089.4(ATP13A2):c.1306+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
ATP13A2
NM_022089.4 splice_donor_5th_base, intron
NM_022089.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 2.31
Genes affected
ATP13A2 (HGNC:30213): (ATPase cation transporting 13A2) This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-16996381-C-T is Pathogenic according to our data. Variant chr1-16996381-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1219.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP13A2 | NM_022089.4 | c.1306+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000326735.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP13A2 | ENST00000326735.13 | c.1306+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_022089.4 | A1 | |||
ENST00000446261.1 | n.188-8262C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2021 | For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 13, but is expected to preserve the integrity of the reading-frame (PMID: 16964263). Experimental studies have shown that this variant affects ATP13A2 protein function (PMID: 21724849, 23499937). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1219). This variant is also known as ATP13A2SKP13. This variant has been observed in individual(s) with clinical features of autosomal recessive Kufor-Rakeb syndrome (PMID: 16964263). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 13 of the ATP13A2 gene. It does not directly change the encoded amino acid sequence of the ATP13A2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. - |
Kufor-Rakeb syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 26, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at