1-17002357-G-T

Variant names:

• chr1-17002357-G-T
• rs372857244
• NM_022089.4:c.574C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000326735.13(ATP13A2):​c.574C>A​(p.Arg192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP13A2 ENST00000326735.13 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, G2P, ClinGen
• 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

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20419106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326735.13. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.574C>A	p.Arg192Ser	missense	Exon 7 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.559C>A	p.Arg187Ser	missense	Exon 7 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.559C>A	p.Arg187Ser	missense	Exon 7 of 27	NP_001135446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.574C>A	p.Arg192Ser	missense	Exon 7 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.559C>A	p.Arg187Ser	missense	Exon 7 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.559C>A	p.Arg187Ser	missense	Exon 7 of 27	ENSP00000341115.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0074
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.28
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.047	B
Vest4		0.46
MutPred		0.48		Loss of catalytic residue at R192 (P = 0.0331)
MVP		0.86
MPC		0.43
ClinPred		0.43	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.63
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs372857244; hg19: chr1-17328852;