rs772870846
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_022089.4(ATP13A2):āc.2899G>Cā(p.Asp967His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,566 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 Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
ATP13A2
NM_022089.4 missense
NM_022089.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 5.49
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a mutagenesis_site Reduced spermine-induced ATPase activity. (size 0) in uniprot entity AT132_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.931
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP13A2 | NM_022089.4 | c.2899G>C | p.Asp967His | missense_variant | 26/29 | ENST00000326735.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP13A2 | ENST00000326735.13 | c.2899G>C | p.Asp967His | missense_variant | 26/29 | 1 | NM_022089.4 | A1 | |
ENST00000446261.1 | n.187+8118C>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461566Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727084
GnomAD4 exome
AF:
AC:
1
AN:
1461566
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
727084
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in the homozygous state in individual(s) with clinical features of spastic paraplegia (Invitae). ClinVar contains an entry for this variant (Variation ID: 533807). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 967 of the ATP13A2 protein (p.Asp967His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0378);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at