chr1-16996008-C-G

Position:

• chr1-16996008-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000326735.13(ATP13A2):​c.1510G>C​(p.Gly504Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP13A2 ENST00000326735.13 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 3.07

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 1-16996008-C-G is Pathogenic according to our data. Variant chr1-16996008-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1510G>C	p.Gly504Arg	missense_variant	15/29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1510G>C	p.Gly504Arg	missense_variant	15/29	1	NM_022089.4	ENSP00000327214	A1
	ENST00000446261.1	n.188-8635C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kufor-Rakeb syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 08, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Neurodegeneration with brain iron accumulation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 22, 2024

Variant summary: ATP13A2 c.1510G>C (p.Gly504Arg) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251098 control chromosomes (gnomAD). c.1510G>C has been reported in the literature in individuals affected with parkinsonism (Montaut_2018, Chien_2021). These data indicate that the variant is likely to be associated with disease. At least three publications reported experimental evidence evaluating an impact on protein function and this variant disrupted protein function (Covy_2012, Podhajska_2012, Matsui_2013). The following publications have been ascertained in the context of this evaluation (PMID: 34475127, 22847264, 23499937, 29913018, 22768177). ClinVar contains an entry for this variant (Variation ID: 1221). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2023

Experimental studies have shown that this missense change affects ATP13A2 function (PMID: 22768177, 22847264, 23499937). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1221). This missense change has been observed in individuals with clinical features of Kufor-Rakeb syndrome or hereditary spastic paraplegia (PMID: 17485642; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 504 of the ATP13A2 protein (p.Gly504Arg). -

See cases Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 04, 2019

ACMG classification criteria: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.;.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.
MutationTaster	Benign	0.92	A;A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N;N;N;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0090	D;D;D;D;.
Sift4G	Benign	0.065	T;D;T;D;T
Polyphen		0.58	P;.;.;.;.
Vest4		0.54
MutPred		0.94		Gain of MoRF binding (P = 0.0106);.;.;.;.;
MVP		0.90
MPC		0.92
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.55
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs121918227; hg19: chr1-17322503;