rs7531163

Positions:

• chr1-16986959-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001061
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.747

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=-0.55).
• BP6: Variant 1-16986959-G-A is Benign according to our data. Variant chr1-16986959-G-A is described in ClinVar as [Benign]. Clinvar id is 128471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16986959-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.3084-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.3084-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_022089.4	ENSP00000327214	A1
	ENST00000446261.1	n.187+7847G>A		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.282 AC: 70700 AN: 250814 Hom.: 11144 AF XY: 0.277 AC XY: 37663 AN XY: 135760

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 SAS exome AF: 0.231

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

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.356

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.534

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.262

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

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.558

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.262

Alfa AF: 0.235 Hom.: 2234

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -

Kufor-Rakeb syndrome Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

Autosomal recessive spastic paraplegia type 78 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2016

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

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

Publications

LitVar

Other links and lift over

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