rs15786

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/16 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.380

Publications

21 publications found

Variant links:

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

ATP13A2 links:

ENSG00000226526 (HGNC:):

ENSG00000226526 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4 link	c.*124C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13 link	c.*124C>T		3_prime_UTR_variant	Exon 29 of 29	1	NM_022089.4	ENSP00000327214.8		Q9NQ11-1

Frequencies

GnomAD3 genomes

AF:

0.0394

AC:

5997

AN:

152062

Hom.:

197

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0397

AC:

6881

AN:

173142

AF XY:

0.0392

show subpopulations

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 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.:

AF XY:

0.0522

AC XY:

36274

AN XY:

694332

show subpopulations

African (AFR)

AF:

0.00874

AC:

281

AN:

32146

American (AMR)

AF:

0.0138

AC:

471

AN:

34128

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

548

AN:

24708

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37756

South Asian (SAS)

AF:

0.0106

AC:

845

AN:

80048

European-Finnish (FIN)

AF:

0.0926

AC:

4664

AN:

50348

Middle Eastern (MID)

AF:

0.00833

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.0605

AC:

65571

AN:

1084084

Other (OTH)

AF:

0.0456

AC:

2657

AN:

58278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

4505

9009

13514

18018

22523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0394

AC:

5996

AN:

152180

Hom.:

197

Cov.:

AF XY:

0.0387

AC XY:

2877

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00958

AC:

398

AN:

41534

American (AMR)

AF:

0.0229

AC:

350

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.00728

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0880

AC:

933

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0609

AC:

4136

AN:

67966

Other (OTH)

AF:

0.0251

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

274

548

821

1095

1369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0508

Hom.:

807

Bravo

AF:

0.0339

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0569

AC:

181

ExAC

AF:

0.0323

AC:

3786

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kufor-Rakeb syndrome

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.20

CADD

Benign

2.5

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.48

PhyloP100

0.38

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0040

.;D

Vest4

0.13

ClinPred

0.0069

GERP RS

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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rs15786

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over