1-16986101-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000341676.9(ATP13A2):c.3361A>T(p.Thr1121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,555,544 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (18 hom.)
• Consequence: ATP13A2 ENST00000341676.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.390

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053931773).
• BP6: Variant 1-16986101-T-A is Benign according to our data. Variant chr1-16986101-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 493023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16986101-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00405 (590/145580) while in subpopulation NFE AF= 0.00626 (413/66022). AF 95% confidence interval is 0.00576. There are 6 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A2	NM_022089.4	c.*120A>T		3_prime_UTR_variant	29/29	ENST00000326735.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP13A2	ENST00000326735.13	c.*120A>T		3_prime_UTR_variant	29/29	1	NM_022089.4	A1
	ENST00000446261.1	n.187+6989T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 590 AN: 145466 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00572

Gnomad ASJ AF: 0.00382

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00219

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.00545

GnomAD3 exomes AF: 0.00350 AC: 615 AN: 175576 Hom.: 1 AF XY: 0.00323 AC XY: 304 AN XY: 94146

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00566

GnomAD4 exome AF: 0.00547 AC: 7708 AN: 1409964 Hom.: 18 Cov.: 31 AF XY: 0.00530 AC XY: 3690 AN XY: 696420

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00388

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000752

Gnomad4 FIN exome AF: 0.00309

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.00405 AC: 590 AN: 145580 Hom.: 6 Cov.: 31 AF XY: 0.00380 AC XY: 269 AN XY: 70882

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00571

Gnomad4 ASJ AF: 0.00382

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00219

Gnomad4 NFE AF: 0.00626

Gnomad4 OTH AF: 0.00539

Alfa AF: 0.00513 Hom.: 0

Bravo AF: 0.00428

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00440 AC: 14

ExAC AF: 0.00285 AC: 338

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATP13A2: PP3, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Kufor-Rakeb syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

ATP13A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	0.48
Dann	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	0.51	D;D;N
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D
Vest4		0.17
MutPred		0.10		Loss of sheet (P = 0.1158);.;
MVP		0.42
ClinPred		0.018	T
GERP RS		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41273151; hg19: chr1-17312596;