chr1-16996298-G-C

Variant names:

• chr1-16996298-G-C
• rs149372969
• NM_022089.4:c.1309C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022089.4(ATP13A2):​c.1309C>G​(p.Leu437Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,210 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: ATP13A2 NM_022089.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 0.0710
• Publications: 4 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022271544).
• BP6: Variant 1-16996298-G-C is Benign according to our data. Variant chr1-16996298-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293793.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.1309C>G	p.Leu437Val	missense splice_region	Exon 14 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.1294C>G	p.Leu432Val	missense splice_region	Exon 14 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.1294C>G	p.Leu432Val	missense splice_region	Exon 14 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.1309C>G	p.Leu437Val	missense splice_region	Exon 14 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.1294C>G	p.Leu432Val	missense splice_region	Exon 14 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.1294C>G	p.Leu432Val	missense splice_region	Exon 14 of 27	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00105 AC: 265 AN: 251284 AF XY: 0.00108

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00143 AC: 2094 AN: 1461874 Hom.: 3 Cov.: 32 AF XY: 0.00147 AC XY: 1072 AN XY: 727240

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000768 AC: 41 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00176 AC: 1959 AN: 1112012

Other (OTH) AF: 0.000828 AC: 50 AN: 60396

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74478

African (AFR) AF: 0.000192 AC: 8 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.000782

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously, using an alternate transcript in one of the cases, in patients with Parkinson disease; however, the variant was also observed in unaffected controls (PMID: 25466404, 38173558); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25466404, 38173558)

Jun 13, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 16, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4

Kufor-Rakeb syndrome Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Feb 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Inborn genetic diseases Uncertain:1

Jan 26, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L437V variant (also known as c.1309C>G), located in coding exon 14 of the ATP13A2 gene, results from a C to G substitution at nucleotide position 1309. The leucine at codon 437 is replaced by valine, an amino acid with highly similar properties. In one study, this p.L437V alteration (resulting from c.1311G>C) was detected in six individuals from the Faroe Islands with Parkinson disease (PD), none of whom carried a second alteration in the ATP13A2 gene. Of these six individuals, one had disease onset at age 28, and also carried alterations of unknown significance in LRRK2 and CNAJC13 (Petersen MS et al. Parkinsonism Relat. Disord., 2015 Jan;21:75-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP13A2-related disorder Benign:1

Apr 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.071
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.24
Sift	Benign	0.22	T
Sift4G	Benign	0.54	T
Polyphen		0.0050	B
Vest4		0.28
MVP		0.77
MPC		0.34
ClinPred		0.0025	T
GERP RS		1.1
PromoterAI		-0.025	Neutral
Varity_R		0.046
gMVP		0.70
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs149372969; hg19: chr1-17322793;