rs56290406

Positions:

• chr1-17000045-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022089.4(ATP13A2):​c.1005C>T​(p.Ala335=) 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

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-17000045-G-A is Benign according to our data. Variant chr1-17000045-G-A is described in ClinVar as [Benign]. Clinvar id is 128463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17000045-G-A is described in Lovd as [Benign]. Variant chr1-17000045-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1005C>T	p.Ala335=	synonymous_variant	11/29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1005C>T	p.Ala335=	synonymous_variant	11/29	1	NM_022089.4	ENSP00000327214	A1
	ENST00000446261.1	n.188-4598G>A		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.0263 AC: 6501 AN: 246884 Hom.: 125 AF XY: 0.0256 AC XY: 3434 AN XY: 134222

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 SAS exome AF: 0.0151

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

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.0360

Gnomad4 OTH exome AF: 0.0326

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

Gnomad4 AFR AF: 0.0644

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0349

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0378 Hom.: 58

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2016

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs56290406; hg19: chr1-17326540;