chr1-16986091-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001141974.3(ATP13A2):c.3371C>T(p.Pro1124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,548,890 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0057 ( 36 hom. )

Consequence

ATP13A2
NM_001141974.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.722

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036759377).

BP6

Variant 1-16986091-G-A is Benign according to our data. Variant chr1-16986091-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293762.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr1-16986091-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00367 (558/152210) while in subpopulation NFE AF= 0.00553 (376/67998). AF 95% confidence interval is 0.00507. There are 7 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4 link	c.*130C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735 link	c.*130C>T		3_prime_UTR_variant	Exon 29 of 29	1	NM_022089.4	ENSP00000327214.8		Q9NQ11-1

Frequencies

GnomAD3 genomes

AF:

0.00367

AC:

558

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00307

AC:

499

AN:

162606

Hom.:

AF XY:

0.00286

AC XY:

249

AN XY:

87048

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00140

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000648

Gnomad NFE exome

AF:

0.00620

Gnomad OTH exome

AF:

0.00415

GnomAD4 exome

AF:

0.00566

AC:

7908

AN:

1396680

Hom.:

Cov.:

AF XY:

0.00551

AC XY:

3793

AN XY:

688316

show subpopulations

Gnomad4 AFR exome

AF:

0.000947

Gnomad4 AMR exome

AF:

0.00126

Gnomad4 ASJ exome

AF:

0.000820

Gnomad4 EAS exome

AF:

0.0000268

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000764

Gnomad4 NFE exome

AF:

0.00693

Gnomad4 OTH exome

AF:

0.00512

GnomAD4 genome

AF:

0.00367

AC:

558

AN:

152210

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00553

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00532

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00727

AC:

ExAC

AF:

0.00211

AC:

245

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 13, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP13A2: PP3, BS2 -

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

Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP13A2 NM_001141974 exon 27 p.Pro1124Leu (c.3371C>T): This variant has not been reported in the literature but is present in 0.5% (460/81050) of European alleles, including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs189334432). This variant is present in ClinVar (Variation ID:293762). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Kufor-Rakeb syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

0.92

DANN

Uncertain

0.99

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.56

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0037

T;T

MetaSVM

Uncertain

0.00050

PROVEAN

Benign

0.13

N;N

REVEL

Benign

0.17

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

.;D

Vest4

0.25

MVP

0.34

ClinPred

0.012

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

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.

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