rs761421

Variant names:

• chr1-16987159-C-T
• rs761421
• NM_022089.4:c.2970G>A

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.2970G>A​(p.Val990Val) 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 1,612,896 control chromosomes in the GnomAD database, including 203,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14650 hom., cov: 33)
  • Exomes 𝑓: 0.50 (188913 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.854
• Publications: 24 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=-0.61).
• BP6: Variant 1-16987159-C-T is Benign according to our data. Variant chr1-16987159-C-T is described in ClinVar as Benign. ClinVar VariationId is 128470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.854 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

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.2970G>A	p.Val990Val	synonymous	Exon 26 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.2955G>A	p.Val985Val	synonymous	Exon 26 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.2838G>A	p.Val946Val	synonymous	Exon 25 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.2970G>A	p.Val990Val	synonymous	Exon 26 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.2955G>A	p.Val985Val	synonymous	Exon 26 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.2838G>A	p.Val946Val	synonymous	Exon 25 of 27	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63475 AN: 151926 Hom.: 14645 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.465 AC: 115513 AN: 248224 AF XY: 0.471

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.504 AC: 735772 AN: 1460852 Hom.: 188913 Cov.: 79 AF XY: 0.504 AC XY: 365963 AN XY: 726744

African (AFR) AF: 0.205 AC: 6869 AN: 33466

American (AMR) AF: 0.475 AC: 21220 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 12648 AN: 26102

East Asian (EAS) AF: 0.305 AC: 12084 AN: 39682

South Asian (SAS) AF: 0.472 AC: 40712 AN: 86236

European-Finnish (FIN) AF: 0.485 AC: 25695 AN: 52970

Middle Eastern (MID) AF: 0.474 AC: 2700 AN: 5700

European-Non Finnish (NFE) AF: 0.526 AC: 585279 AN: 1111694

Other (OTH) AF: 0.473 AC: 28565 AN: 60346

GnomAD4 genome AF: 0.418 AC: 63492 AN: 152044 Hom.: 14650 Cov.: 33 AF XY: 0.413 AC XY: 30710 AN XY: 74276

African (AFR) AF: 0.220 AC: 9142 AN: 41492

American (AMR) AF: 0.447 AC: 6840 AN: 15286

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

East Asian (EAS) AF: 0.274 AC: 1413 AN: 5160

South Asian (SAS) AF: 0.453 AC: 2186 AN: 4822

European-Finnish (FIN) AF: 0.474 AC: 5005 AN: 10568

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35808 AN: 67928

Other (OTH) AF: 0.426 AC: 900 AN: 2114

Alfa AF: 0.491 Hom.: 11599

Bravo AF: 0.407

Asia WGS AF: 0.339 AC: 1178 AN: 3478

EpiCase AF: 0.516

EpiControl AF: 0.518

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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 71% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 66. Only high quality variants are reported.

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University 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

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:4

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 19, 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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Kufor-Rakeb syndrome Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.12
DANN	Benign	0.90
PhyloP100		-0.85
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: rs761421; hg19: chr1-17313654; COSMIC: COSV58699127; COSMIC: COSV58699127;