rs9435659

Variant names:

• chr1-16986848-G-A
• rs9435659
• NM_022089.4:c.3192C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16986848-G-A
• chr1-16986848-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022089.4(ATP13A2):​c.3192C>T​(p.Ala1064Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,386 control chromosomes in the GnomAD database, including 204,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14514 hom., cov: 32)
  • Exomes 𝑓: 0.50 (190267 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.360
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-16986848-G-A is Benign according to our data. Variant chr1-16986848-G-A is described in ClinVar as Benign. ClinVar VariationId is 128473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.3192C>T	p.Ala1064Ala	synonymous_variant	Exon 27 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.3192C>T	p.Ala1064Ala	synonymous_variant	Exon 27 of 29	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62590 AN: 151924 Hom.: 14510 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.465 AC: 115999 AN: 249358 AF XY: 0.471

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.478

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.505 AC: 737963 AN: 1461344 Hom.: 190267 Cov.: 74 AF XY: 0.505 AC XY: 367109 AN XY: 726996

African (AFR) AF: 0.178 AC: 5955 AN: 33478

American (AMR) AF: 0.474 AC: 21175 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 12666 AN: 26130

East Asian (EAS) AF: 0.307 AC: 12200 AN: 39690

South Asian (SAS) AF: 0.472 AC: 40721 AN: 86230

European-Finnish (FIN) AF: 0.487 AC: 25909 AN: 53236

Middle Eastern (MID) AF: 0.473 AC: 2724 AN: 5758

European-Non Finnish (NFE) AF: 0.529 AC: 587993 AN: 1111804

Other (OTH) AF: 0.474 AC: 28620 AN: 60376

GnomAD4 genome AF: 0.412 AC: 62591 AN: 152042 Hom.: 14514 Cov.: 32 AF XY: 0.408 AC XY: 30310 AN XY: 74304

African (AFR) AF: 0.194 AC: 8044 AN: 41506

American (AMR) AF: 0.448 AC: 6846 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1643 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1445 AN: 5134

South Asian (SAS) AF: 0.453 AC: 2179 AN: 4812

European-Finnish (FIN) AF: 0.475 AC: 5021 AN: 10578

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35960 AN: 67940

Other (OTH) AF: 0.424 AC: 897 AN: 2116

Alfa AF: 0.477 Hom.: 8499

Bravo AF: 0.400

Asia WGS AF: 0.340 AC: 1182 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. Only high quality variants are reported. -

not provided Benign:4

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Kufor-Rakeb syndrome Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive spastic paraplegia type 78 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.68
DANN	Benign	0.76
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs9435659; hg19: chr1-17313343; COSMIC: COSV58700662; COSMIC: COSV58700662;