rs137853967

Positions:

• chr1-16986864-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PP3_Moderate PP5_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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.44

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_022089.4 (ATP13A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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 id is 1728485.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-16986864-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.3176T>G	p.Leu1059Arg	missense_variant	27/29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.3176T>G	p.Leu1059Arg	missense_variant	27/29	1	NM_022089.4	ENSP00000327214	A1
	ENST00000446261.1	n.187+7752A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2017

The p.L1059R variant (also known as c.3176T>G), located in coding exon 27 of the ATP13A2 gene, results from a T to G substitution at nucleotide position 3176. The leucine at codon 1059 is replaced by arginine, an amino acid with dissimilar properties. This variant has been observed in trans with a frameshift mutation in two siblings with Kufor-Rakeb syndrome (KRS) and was observed to results in mislocalization of the ATP13A2 protein (Park JS et al. Hum. Mutat., 2011 Aug;32:956-64). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.80		Gain of MoRF binding (P = 0.0681);.;.;.;
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs137853967; hg19: chr1-17313359;