rs200587951

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000326735.13(ATP13A2):​c.106-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,614,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00097 ( 1 hom. )

Consequence

ATP13A2
ENST00000326735.13 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00009074
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: -3.15
Variant links:
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_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 1-17005564-C-T is Benign according to our data. Variant chr1-17005564-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210379.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3, Likely_benign=2}. Variant chr1-17005564-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP13A2NM_022089.4 linkuse as main transcriptc.106-8G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000326735.13 NP_071372.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP13A2ENST00000326735.13 linkuse as main transcriptc.106-8G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_022089.4 ENSP00000327214 A1Q9NQ11-1
ENST00000617114.5 linkuse as main transcriptc.125-8G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 ENSP00000478781 P1

Frequencies

GnomAD3 genomes
AF:
0.000716
AC:
109
AN:
152244
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00132
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00115
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000925
AC:
232
AN:
250896
Hom.:
0
AF XY:
0.000950
AC XY:
129
AN XY:
135788
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.000496
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00148
Gnomad NFE exome
AF:
0.00160
Gnomad OTH exome
AF:
0.000817
GnomAD4 exome
AF:
0.000974
AC:
1424
AN:
1461864
Hom.:
1
Cov.:
33
AF XY:
0.000991
AC XY:
721
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.000306
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00182
Gnomad4 NFE exome
AF:
0.00112
Gnomad4 OTH exome
AF:
0.000844
GnomAD4 genome
AF:
0.000716
AC:
109
AN:
152244
Hom.:
0
Cov.:
33
AF XY:
0.000686
AC XY:
51
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00132
Gnomad4 NFE
AF:
0.00115
Gnomad4 OTH
AF:
0.00191
Alfa
AF:
0.00108
Hom.:
0
Bravo
AF:
0.000563

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023ATP13A2: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 08, 2024Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 16, 2018- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Kufor-Rakeb syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 28, 2014- -
Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 08, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.13
DANN
Benign
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000091
dbscSNV1_RF
Benign
0.010
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200587951; hg19: chr1-17332059; API