dbSNP rs137853967: ATP13A2:p.Leu1059Arg (chr1-16986864-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_022089.4(ATP13A2):c.3176T>G(p.Leu1059Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1059F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP13A2
NM_022089.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.44

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

Kufor-Rakeb syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina
autosomal recessive spastic paraplegia type 78
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
parkinsonism due to ATP13A2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATP13A2 links:

ENSG00000226526 (HGNC:):

ENSG00000226526 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 1-16986864-A-C is Pathogenic according to our data. Variant chr1-16986864-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1728485.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP13A2	NM_022089.4	MANE Select	c.3176T>G	p.Leu1059Arg	missense	Exon 27 of 29	NP_071372.1	Q9NQ11-1
ATP13A2	NM_001141973.3		c.3161T>G	p.Leu1054Arg	missense	Exon 27 of 29	NP_001135445.1	Q9NQ11-3
ATP13A2	NM_001141974.3		c.3044T>G	p.Leu1015Arg	missense	Exon 26 of 27	NP_001135446.1	Q9NQ11-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3176T>G	p.Leu1059Arg	missense	Exon 27 of 29	ENSP00000327214.8	Q9NQ11-1
ATP13A2	ENST00000452699.5	TSL:1	c.3161T>G	p.Leu1054Arg	missense	Exon 27 of 29	ENSP00000413307.1	Q9NQ11-3
ATP13A2	ENST00000341676.9	TSL:1	c.3044T>G	p.Leu1015Arg	missense	Exon 26 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.6

PhyloP100

8.4

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.99

MutPred

0.80

Gain of MoRF binding (P = 0.0681)

MVP

0.93

MPC

1.3

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.92

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over