rs1801334

Variant names:

Variant summary

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

The NM_004562.3(PRKN):c.1180G>A(p.Asp394Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0341 in 1,613,134 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts 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. D394G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.025 ( 64 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1086 hom. )

Consequence

PRKN
NM_004562.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.29

Publications

44 publications found

Variant links:

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PRKN Gene-Disease associations (from GenCC):

autosomal recessive juvenile Parkinson disease 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
Parkinson disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
young-onset Parkinson disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PRKN 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=0.0038829148).

BP6

Variant 6-161360193-C-T is Benign according to our data. Variant chr6-161360193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41222.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 = 0.025 (3807/152308) while in subpopulation NFE AF = 0.0378 (2571/68026). AF 95% confidence interval is 0.0366. There are 64 homozygotes in GnomAd4. There are 1837 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3 link	c.1180G>A	p.Asp394Asn	missense_variant	Exon 11 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6 link	c.1180G>A	p.Asp394Asn	missense_variant	Exon 11 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3810

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00914

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0507

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0378

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0255

AC:

6405

AN:

251482

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0383

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0336

Gnomad NFE exome

AF:

0.0391

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0350

AC:

51172

AN:

1460826

Hom.:

1086

Cov.:

AF XY:

0.0341

AC XY:

24749

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.00827

AC:

277

AN:

33476

American (AMR)

AF:

0.0126

AC:

564

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0388

AC:

1015

AN:

26128

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00371

AC:

320

AN:

86242

European-Finnish (FIN)

AF:

0.0334

AC:

1782

AN:

53410

Middle Eastern (MID)

AF:

0.00920

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0408

AC:

45279

AN:

1111022

Other (OTH)

AF:

0.0311

AC:

1879

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

2364

4729

7093

9458

11822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1668

3336

5004

6672

8340

<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:

0.0250

AC:

3807

AN:

152308

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1837

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00912

AC:

379

AN:

41566

American (AMR)

AF:

0.0142

AC:

217

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

176

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00331

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0334

AC:

355

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0378

AC:

2571

AN:

68026

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

193

386

578

771

964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0337

Hom.:

264

Bravo

AF:

0.0239

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0443

AC:

381

ExAC

AF:

0.0256

AC:

3108

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0381

EpiControl

AF:

0.0372

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive juvenile Parkinson disease 2

Benign:2

Apr 17, 2001

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Lung cancer;C0919267:Ovarian neoplasm;C1868675:Autosomal recessive juvenile Parkinson disease 2

Benign:1

Oct 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

D;.;.;.;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.85

T;T;T;T;.;T

MetaRNN

Benign

0.0039

T;T;T;T;T;T

MetaSVM

Uncertain

0.0043

PhyloP100

4.3

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.4

D;D;D;.;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.023

D;D;T;.;T;T

Sift4G

Benign

0.071

T;T;T;T;T;T

Polyphen

0.56

P;.;.;.;.;.

Vest4

0.27

MPC

0.063

ClinPred

0.044

GERP RS

4.0

Varity_R

0.40

gMVP

0.71

Mutation Taster

=88/12

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