rs55689004

Positions:

• chr1-16997010-C-T

Variant summary

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

The NM_022089.4(ATP13A2):​c.1195+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,610,702 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (45 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.576

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 (BayesDel_noAF=-0.88).
• BP6: Variant 1-16997010-C-T is Benign according to our data. Variant chr1-16997010-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16997010-C-T is described in Lovd as [Likely_benign]. Variant chr1-16997010-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00561 (855/152324) while in subpopulation NFE AF= 0.00607 (413/68038). AF 95% confidence interval is 0.00559. There are 7 homozygotes in gnomad4. There are 480 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1195+10G>A		intron_variant		ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1195+10G>A		intron_variant		1	NM_022089.4	ENSP00000327214	A1
	ENST00000446261.1	n.188-7633C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152206 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00627 AC: 1540 AN: 245694 Hom.: 8 AF XY: 0.00595 AC XY: 794 AN XY: 133470

Gnomad AFR exome AF: 0.000440

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00143

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.00565

Gnomad OTH exome AF: 0.00830

GnomAD4 exome AF: 0.00535 AC: 7806 AN: 1458378 Hom.: 45 Cov.: 33 AF XY: 0.00539 AC XY: 3909 AN XY: 725460

Gnomad4 AFR exome AF: 0.000779

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.000707

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.00483

Gnomad4 OTH exome AF: 0.00640

GnomAD4 genome AF: 0.00561 AC: 855 AN: 152324 Hom.: 7 Cov.: 32 AF XY: 0.00645 AC XY: 480 AN XY: 74472

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00640 Hom.: 4

Bravo AF: 0.00360

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -
Likely 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	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Kufor-Rakeb syndrome Benign:2

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

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 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.48

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: rs55689004; hg19: chr1-17323505;