rs7531163

Variant names:

• chr1-16986959-G-A
• rs7531163
• NM_022089.4:c.3084-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16986959-G-A
• chr1-16986959-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022089.4(ATP13A2):​c.3084-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,342 control chromosomes in the GnomAD database, including 53,206 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4955 hom., cov: 29)
  • Exomes 𝑓: 0.25 (48251 hom.)
• Consequence: ATP13A2 NM_022089.4 splice_region, intron
• Scores: Splicing: ADA: 0.001061
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.747
• Publications: 18 publications found

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]

ATP13A2 Gene-Disease associations (from GenCC):

• Kufor-Rakeb syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, G2P, ClinGen
• autosomal recessive spastic paraplegia type 78

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• parkinsonism due to ATP13A2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-16986959-G-A is Benign according to our data. Variant chr1-16986959-G-A is described in ClinVar as Benign. ClinVar VariationId is 128471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.3084-3C>T		splice_region_variant, intron_variant	Intron 26 of 28	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.3084-3C>T		splice_region_variant, intron_variant	Intron 26 of 28	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36781 AN: 151530 Hom.: 4944 Cov.: 29

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.282 AC: 70700 AN: 250814 AF XY: 0.277

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.250 AC: 365088 AN: 1461694 Hom.: 48251 Cov.: 66 AF XY: 0.249 AC XY: 181231 AN XY: 727176

African (AFR) AF: 0.166 AC: 5556 AN: 33474

American (AMR) AF: 0.356 AC: 15899 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6866 AN: 26128

East Asian (EAS) AF: 0.534 AC: 21197 AN: 39694

South Asian (SAS) AF: 0.236 AC: 20318 AN: 86256

European-Finnish (FIN) AF: 0.310 AC: 16530 AN: 53366

Middle Eastern (MID) AF: 0.276 AC: 1591 AN: 5766

European-Non Finnish (NFE) AF: 0.235 AC: 261319 AN: 1111910

Other (OTH) AF: 0.262 AC: 15812 AN: 60390

GnomAD4 genome AF: 0.243 AC: 36817 AN: 151648 Hom.: 4955 Cov.: 29 AF XY: 0.251 AC XY: 18579 AN XY: 74050

African (AFR) AF: 0.166 AC: 6861 AN: 41388

American (AMR) AF: 0.338 AC: 5155 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 971 AN: 3468

East Asian (EAS) AF: 0.558 AC: 2829 AN: 5068

South Asian (SAS) AF: 0.244 AC: 1168 AN: 4786

European-Finnish (FIN) AF: 0.321 AC: 3371 AN: 10508

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15637 AN: 67878

Other (OTH) AF: 0.262 AC: 551 AN: 2104

Alfa AF: 0.235 Hom.: 2373

Bravo AF: 0.244

Asia WGS AF: 0.363 AC: 1262 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.249

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 47% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 44. Only high quality variants are reported. -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kufor-Rakeb syndrome Benign:3

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive spastic paraplegia type 78 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Feb 24, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.0
DANN	Benign	0.71
PhyloP100		0.75
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.10
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

Other links and lift over

dbSNP: rs7531163; hg19: chr1-17313454; COSMIC: COSV104399909; COSMIC: COSV104399909;