rs56290406

Variant names:

• chr1-17000045-G-A
• rs56290406
• NM_022089.4:c.1005C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022089.4(ATP13A2):​c.1005C>T​(p.Ala335Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,612,546 control chromosomes in the GnomAD database, including 1,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (144 hom., cov: 33)
  • Exomes 𝑓: 0.033 (959 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.46
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• BP6: Variant 1-17000045-G-A is Benign according to our data. Variant chr1-17000045-G-A is described in ClinVar as Benign. ClinVar VariationId is 128463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1005C>T	p.Ala335Ala	synonymous_variant	Exon 11 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1005C>T	p.Ala335Ala	synonymous_variant	Exon 11 of 29	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5914 AN: 152150 Hom.: 144 Cov.: 33

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0263 AC: 6501 AN: 246884 AF XY: 0.0256

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0332 AC: 48442 AN: 1460278 Hom.: 959 Cov.: 32 AF XY: 0.0322 AC XY: 23387 AN XY: 726286

African (AFR) AF: 0.0709 AC: 2372 AN: 33468

American (AMR) AF: 0.0154 AC: 686 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0278 AC: 725 AN: 26088

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.0155 AC: 1334 AN: 86124

European-Finnish (FIN) AF: 0.0229 AC: 1206 AN: 52742

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5766

European-Non Finnish (NFE) AF: 0.0360 AC: 40050 AN: 1111434

Other (OTH) AF: 0.0326 AC: 1965 AN: 60312

GnomAD4 genome AF: 0.0389 AC: 5918 AN: 152268 Hom.: 144 Cov.: 33 AF XY: 0.0381 AC XY: 2836 AN XY: 74452

African (AFR) AF: 0.0644 AC: 2675 AN: 41540

American (AMR) AF: 0.0227 AC: 347 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4824

European-Finnish (FIN) AF: 0.0233 AC: 248 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2372 AN: 68016

Other (OTH) AF: 0.0393 AC: 83 AN: 2110

Alfa AF: 0.0340 Hom.: 177

Bravo AF: 0.0396

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0296

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

Jun 29, 2017

Athena Diagnostics

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

not provided Benign:3

May 15, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 17, 2018

GeneDx

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

Mar 18, 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.

Kufor-Rakeb syndrome Benign:1

Jan 12, 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.15
DANN	Benign	0.77
PhyloP100		-4.5
PromoterAI		-0.0096	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs56290406; hg19: chr1-17326540;