NM_007262.5:c.293G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007262.5(PARK7):c.293G>A(p.Arg98Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00932 in 1,614,132 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0071 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 99 hom. )

Consequence

PARK7
NM_007262.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.37

Publications

52 publications found

Variant links:

Genes affected

PARK7 (HGNC:16369): (Parkinsonism associated deglycase) The product of this gene belongs to the peptidase C56 family of proteins. It acts as a positive regulator of androgen receptor-dependent transcription. It may also function as a redox-sensitive chaperone, as a sensor for oxidative stress, and it apparently protects neurons against oxidative stress and cell death. Defects in this gene are the cause of autosomal recessive early-onset Parkinson disease 7. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

PARK7 Gene-Disease associations (from GenCC):

Parkinson disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive early-onset Parkinson disease 7
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
young-onset Parkinson disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PARK7 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=0.007415414).

BP6

Variant 1-7970934-G-A is Benign according to our data. Variant chr1-7970934-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00715 (1088/152266) while in subpopulation NFE AF = 0.0114 (774/68014). AF 95% confidence interval is 0.0107. There are 5 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARK7	NM_007262.5 link	c.293G>A	p.Arg98Gln	missense_variant	Exon 5 of 7	ENST00000338639.10	NP_009193.2	Q99497V9HWC2
PARK7	NM_001123377.2 link	c.293G>A	p.Arg98Gln	missense_variant	Exon 5 of 7		NP_001116849.1	Q99497V9HWC2
PARK7	XM_005263424.4 link	c.293G>A	p.Arg98Gln	missense_variant	Exon 5 of 7		XP_005263481.1	Q99497V9HWC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10 link	c.293G>A	p.Arg98Gln	missense_variant	Exon 5 of 7	1	NM_007262.5	ENSP00000340278.5		Q99497

Frequencies

GnomAD3 genomes

AF:

0.00715

AC:

1088

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.00789

AC:

1984

AN:

251484

AF XY:

0.00853

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00598

Gnomad ASJ exome

AF:

0.00982

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00879

GnomAD4 exome

AF:

0.00955

AC:

13957

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00970

AC XY:

7051

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.00606

AC:

271

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

289

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0122

AC:

1055

AN:

86256

European-Finnish (FIN)

AF:

0.00127

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0189

AC:

109

AN:

5768

European-Non Finnish (NFE)

AF:

0.0104

AC:

11537

AN:

1111994

Other (OTH)

AF:

0.00940

AC:

568

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

786

1572

2358

3144

3930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

432

864

1296

1728

2160

<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:

0.00715

AC:

1088

AN:

152266

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

483

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41554

American (AMR)

AF:

0.00660

AC:

101

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00894

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0108

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

774

AN:

68014

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00931

Hom.:

Bravo

AF:

0.00706

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00815

AC:

989

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PARK7: BP4, BS1, BS2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25466404, 16997464, 27535533, 17504761, 15254937, 15790532, 26274610, 27884173, 27592010, 12891685, 22428580, 22995991, 22960331, 15219840, 22173095, 14705128) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive early-onset Parkinson disease 7

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Renal cysts and diabetes syndrome

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Arg98Gln variant in PARK7 has been identified in 3 individuals with Parkinson disease (PMID: 12891685, 14705128), but has also been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg98Gln variant may impact protein function (PMID: 22428580, 15219840, 15790532). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive Parkinson disease. -

PARK7-related disorder

Benign:1

Mar 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.21

T;T;T;T;T;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

.;.;.;T;.;T;T

MetaRNN

Benign

0.0074

T;T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.56

N;N;N;.;N;N;.

PhyloP100

5.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.23

.;N;N;.;N;N;.

REVEL

Benign

0.20

Sift

Benign

0.51

.;T;T;.;T;T;.

Sift4G

Benign

0.62

T;T;T;T;T;T;T

Polyphen

0.0050

B;B;B;.;B;B;.

Vest4

0.40, 0.37, 0.38

MVP

0.60

MPC

0.15

ClinPred

0.0021

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.66

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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