1-16986091-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000341676.9(ATP13A2):c.3371C>T(p.Pro1124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,548,890 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (36 hom.)
• Consequence: ATP13A2 ENST00000341676.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.722

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036759377).
• BP6: Variant 1-16986091-G-A is Benign according to our data. Variant chr1-16986091-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293762.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr1-16986091-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00367 (558/152210) while in subpopulation NFE AF= 0.00553 (376/67998). AF 95% confidence interval is 0.00507. There are 7 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A2	NM_022089.4	c.*130C>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.*130C>T		3_prime_UTR_variant	29/29	1	NM_022089.4	A1
	ENST00000446261.1	n.187+6979G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 558 AN: 152092 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00307 AC: 499 AN: 162606 Hom.: 2 AF XY: 0.00286 AC XY: 249 AN XY: 87048

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000648

Gnomad NFE exome AF: 0.00620

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00566 AC: 7908 AN: 1396680 Hom.: 36 Cov.: 31 AF XY: 0.00551 AC XY: 3793 AN XY: 688316

Gnomad4 AFR exome AF: 0.000947

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.000820

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000764

Gnomad4 NFE exome AF: 0.00693

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.00367 AC: 558 AN: 152210 Hom.: 7 Cov.: 31 AF XY: 0.00320 AC XY: 238 AN XY: 74414

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00553

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00532 Hom.: 1

Bravo AF: 0.00430

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00727 AC: 28

ExAC AF: 0.00211 AC: 245

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATP13A2: PP3, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

ATP13A2 NM_001141974 exon 27 p.Pro1124Leu (c.3371C>T): This variant has not been reported in the literature but is present in 0.5% (460/81050) of European alleles, including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs189334432). This variant is present in ClinVar (Variation ID:293762). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Kufor-Rakeb syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	0.92
Dann	Uncertain	0.99
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.56	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0037	T;T
MetaSVM	Uncertain	0.00050	D
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D
Vest4		0.25
MVP		0.34
ClinPred		0.012	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs189334432; hg19: chr1-17312586;