rs117758987

chr1-16997011-G-A

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+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,610,980 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (36 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.176

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 1-16997011-G-A is Benign according to our data. Variant chr1-16997011-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 293797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16997011-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00264 (402/152286) while in subpopulation EAS AF= 0.04 (207/5174). AF 95% confidence interval is 0.0355. There are 6 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. 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.1195+9C>T		intron_variant		ENST00000326735.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1195+9C>T		intron_variant		1	NM_022089.4	A1
	ENST00000446261.1	n.188-7632G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152168 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00453 AC: 1115 AN: 246302 Hom.: 25 AF XY: 0.00431 AC XY: 577 AN XY: 133744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00161 AC: 2348 AN: 1458694 Hom.: 36 Cov.: 33 AF XY: 0.00160 AC XY: 1162 AN XY: 725606

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0394

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00979

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152286 Hom.: 6 Cov.: 31 AF XY: 0.00377 AC XY: 281 AN XY: 74444

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0400

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000595

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2018	- -

ATP13A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Kufor-Rakeb syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	8.2
Dann	Benign	0.49

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: rs117758987; hg19: chr1-17323506; COSMIC: COSV58702436; COSMIC: COSV58702436;