1-16986248-C-T

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.3214G>A(p.Ala1072Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,608,170 control chromosomes in the GnomAD database, including 201,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1072A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 14378 hom., cov: 32)

Exomes 𝑓: 0.50 ( 187281 hom. )

Consequence

ATP13A2
ENST00000341676.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -2.77

Publications

41 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=4.451812E-5).

BP6

Variant 1-16986248-C-T is Benign according to our data. Variant chr1-16986248-C-T is described in ClinVar as Benign. ClinVar VariationId is 128475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4 link	c.3516G>A	p.Pro1172Pro	synonymous_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.3516G>A	p.Pro1172Pro	synonymous_variant	Exon 29 of 29	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes

AF:

0.411

AC:

62322

AN:

151636

Hom.:

14373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.482

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.464

Gnomad EAS

AF:

0.276

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.475

Gnomad MID

AF:

0.417

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.424

GnomAD2 exomes

AF:

0.470

AC:

110330

AN:

234588

AF XY:

0.476

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.485

Gnomad ASJ exome

AF:

0.475

Gnomad EAS exome

AF:

0.295

Gnomad FIN exome

AF:

0.487

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.471

GnomAD4 exome

AF:

0.502

AC:

731283

AN:

1456418

Hom.:

187281

Cov.:

AF XY:

0.502

AC XY:

363475

AN XY:

724118

show subpopulations

African (AFR)

AF:

0.182

AC:

6092

AN:

33424

American (AMR)

AF:

0.478

AC:

20991

AN:

43884

Ashkenazi Jewish (ASJ)

AF:

0.475

AC:

12286

AN:

25874

East Asian (EAS)

AF:

0.304

AC:

12007

AN:

39438

South Asian (SAS)

AF:

0.459

AC:

39262

AN:

85492

European-Finnish (FIN)

AF:

0.488

AC:

25636

AN:

52546

Middle Eastern (MID)

AF:

0.464

AC:

2607

AN:

5614

European-Non Finnish (NFE)

AF:

0.526

AC:

584131

AN:

1110064

Other (OTH)

AF:

0.471

AC:

28271

AN:

60082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

24269

48538

72806

97075

121344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16562

33124

49686

66248

82810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.411

AC:

62332

AN:

151752

Hom.:

14378

Cov.:

AF XY:

0.407

AC XY:

30172

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.198

AC:

8189

AN:

41300

American (AMR)

AF:

0.446

AC:

6818

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

1610

AN:

3470

East Asian (EAS)

AF:

0.275

AC:

1413

AN:

5130

South Asian (SAS)

AF:

0.434

AC:

2094

AN:

4820

European-Finnish (FIN)

AF:

0.475

AC:

5014

AN:

10562

Middle Eastern (MID)

AF:

0.428

AC:

125

AN:

292

European-Non Finnish (NFE)

AF:

0.527

AC:

35745

AN:

67884

Other (OTH)

AF:

0.419

AC:

885

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1726

3453

5179

6906

8632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.488

Hom.:

20700

Bravo

AF:

0.399

TwinsUK

AF:

0.527

AC:

1955

ALSPAC

AF:

0.523

AC:

2015

ESP6500AA

AF:

0.217

AC:

944

ESP6500EA

AF:

0.526

AC:

4491

ExAC

AF:

0.455

AC:

54634

Asia WGS

AF:

0.333

AC:

1158

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 72% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 67. Only high quality variants are reported. -

not provided

Benign:4

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Kufor-Rakeb syndrome

Benign:3

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Jan 08, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.030

CADD

Benign

0.21

(source)

DANN

Benign

0.80

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.000045

T;T

MetaSVM

Benign

-1.0

PhyloP100

-2.8

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.24

Sift

Benign

0.99

T;T

Sift4G

Benign

0.60

.;T

Vest4

0.12

ClinPred

0.0029

GERP RS

-7.1

Mutation Taster

=97/3

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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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