1-17000272-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_022089.4(ATP13A2):c.881G>A(p.Arg294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,577,728 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 31)

Exomes 𝑓: 0.015 ( 198 hom. )

Consequence

ATP13A2
NM_022089.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:14

Conservation

PhyloP100: -0.400

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]

ATP13A2 links:

ENSG00000226526 (HGNC:):

ENSG00000226526 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 1-17000272-C-T is Benign according to our data. Variant chr1-17000272-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17000272-C-T is described in Lovd as [Likely_benign]. Variant chr1-17000272-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1789/151912) while in subpopulation NFE AF= 0.0163 (1108/67922). AF 95% confidence interval is 0.0155. There are 22 homozygotes in gnomad4. There are 857 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4 link	c.881G>A	p.Arg294Gln	missense_variant	Exon 10 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13 link	c.881G>A	p.Arg294Gln	missense_variant	Exon 10 of 29	1	NM_022089.4	ENSP00000327214.8		Q9NQ11-1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1790

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00283

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00291

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0178

GnomAD3 exomes

AF:

0.0117

AC:

2284

AN:

195112

Hom.:

AF XY:

0.0118

AC XY:

1232

AN XY:

104410

show subpopulations

Gnomad AFR exome

AF:

0.00196

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.0381

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00416

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0172

GnomAD4 exome

AF:

0.0152

AC:

21696

AN:

1425816

Hom.:

198

Cov.:

AF XY:

0.0150

AC XY:

10587

AN XY:

705760

show subpopulations

Gnomad4 AFR exome

AF:

0.00241

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.0387

Gnomad4 EAS exome

AF:

0.000158

Gnomad4 SAS exome

AF:

0.00412

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.0166

Gnomad4 OTH exome

AF:

0.0170

GnomAD4 genome

AF:

0.0118

AC:

1789

AN:

151912

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

857

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.00282

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.000390

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0163

Gnomad4 OTH

AF:

0.0176

Alfa

AF:

0.0149

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.00812

AC:

975

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP13A2: BP4, BS1, BS2 -

Oct 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27294386, 19705361, 22743658, 22995991) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:5

Jan 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Kufor-Rakeb syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;.;.;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.78

T;T;T;T;T;T

MetaRNN

Benign

0.0058

T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

L;.;.;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.37

N;N;N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.16

T;T;T;.;T;T

Sift4G

Benign

0.48

T;T;T;T;T;.

Polyphen

0.080

B;.;.;.;.;.

Vest4

0.25

MPC

0.37

ClinPred

0.0042

GERP RS

-0.71

Varity_R

0.026

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: -1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over