ATP13A2 p.Val578Gly

Variant names:

• chr1-16993645-A-C
• rs56186751
• NM_022089.4:c.1733T>G
• ATP13A2 p.Val578Gly

Your query was ambiguous. Multiple possible variants found:

• chr1-16993645-A-C
• chr1-16993644-CA-AC
• chr1-16993644-CA-GC
• chr1-16993644-CA-TC

Variant summary

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

The NM_022089.4(ATP13A2):​c.1733T>G​(p.Val578Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.83
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Illumina
• autosomal recessive spastic paraplegia type 78

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• parkinsonism due to ATP13A2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.1733T>G	p.Val578Gly	missense	Exon 16 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.1718T>G	p.Val573Gly	missense	Exon 16 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.1718T>G	p.Val573Gly	missense	Exon 16 of 27	NP_001135446.1	Q9NQ11-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.1733T>G	p.Val578Gly	missense	Exon 16 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.1718T>G	p.Val573Gly	missense	Exon 16 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.1718T>G	p.Val573Gly	missense	Exon 16 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Varity_R		0.86
gMVP		0.79
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56186751;

hg19: chr1-17320140;