rs772414750

Variant names:

• chr1-17000275-A-G
• rs772414750
• NM_022089.4:c.878T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022089.4(ATP13A2):​c.878T>C​(p.Met293Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,434,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.05

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]

ENSG00000226526 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0683935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.878T>C	p.Met293Thr	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	c.878T>C	p.Met293Thr	missense_variant	Exon 10 of 29	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.0000289 AC: 4 AN: 138258 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000614

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 14 AN: 1295934 Hom.: 0 Cov.: 37 AF XY: 0.00000781 AC XY: 5 AN XY: 640430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000289 AC: 4 AN: 138258 Hom.: 0 Cov.: 31 AF XY: 0.0000302 AC XY: 2 AN XY: 66270

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000614

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000726 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP13A2 protein function. This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 293 of the ATP13A2 protein (p.Met293Thr). This variant is present in population databases (rs772414750, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP13A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 567424). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.878T>C (p.M293T) alteration is located in exon 10 (coding exon 10) of the ATP13A2 gene. This alteration results from a T to C substitution at nucleotide position 878, causing the methionine (M) at amino acid position 293 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.23	T;.;.;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.60	T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.068	T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.97	N;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.43	N;N;N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.20	T;T;T;.;T;T
Sift4G	Benign	0.34	T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.18
MutPred		0.55		Gain of phosphorylation at M293 (P = 0.0241);.;.;.;.;.;
MVP		0.71
MPC		0.37
ClinPred		0.044	T
GERP RS		3.7
Varity_R		0.037
gMVP		0.42

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: rs772414750; hg19: chr1-17326770;