rs15786

chr1-16986097-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000341676.9(ATP13A2):c.3365C>T(p.Pro1122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,559,316 control chromosomes in the GnomAD database, including 2,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (197 hom., cov: 31)
  • Exomes 𝑓: 0.053 (2365 hom.)
• Consequence: ATP13A2 ENST00000341676.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.380

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 (MetaRNN=0.0023908615).
• BP6: Variant 1-16986097-G-A is Benign according to our data. Variant chr1-16986097-G-A is described in ClinVar as [Benign]. Clinvar id is 293763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16986097-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A2	NM_022089.4	c.*124C>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.*124C>T		3_prime_UTR_variant	29/29	1	NM_022089.4	A1
	ENST00000446261.1	n.187+6985G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5997 AN: 152062 Hom.: 197 Cov.: 31

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0608

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0397 AC: 6881 AN: 173142 Hom.: 221 AF XY: 0.0392 AC XY: 3644 AN XY: 92942

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00992

Gnomad FIN exome AF: 0.0911

Gnomad NFE exome AF: 0.0598

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0534 AC: 75085 AN: 1407136 Hom.: 2365 Cov.: 31 AF XY: 0.0522 AC XY: 36274 AN XY: 694332

Gnomad4 AFR exome AF: 0.00874

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0926

Gnomad4 NFE exome AF: 0.0605

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0394 AC: 5996 AN: 152180 Hom.: 197 Cov.: 31 AF XY: 0.0387 AC XY: 2877 AN XY: 74402

Gnomad4 AFR AF: 0.00958

Gnomad4 AMR AF: 0.0229

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00728

Gnomad4 FIN AF: 0.0880

Gnomad4 NFE AF: 0.0609

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0499 Hom.: 411

Bravo AF: 0.0339

ESP6500AA AF: 0.0116 AC: 16

ESP6500EA AF: 0.0569 AC: 181

ExAC AF: 0.0323 AC: 3786

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kufor-Rakeb syndrome Benign:1

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 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	2.5
Dann	Uncertain	0.98
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	0.99	D;D;N
PROVEAN	Benign	0.38	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Vest4		0.13
ClinPred		0.0069	T
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs15786; hg19: chr1-17312592;