6-162201165-C-T

Variant names:

Variant summary

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

The NM_004562.3(PRKN):c.500G>A(p.Ser167Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,996 control chromosomes in the GnomAD database, including 4,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 678 hom., cov: 32)

Exomes 𝑓: 0.036 ( 4198 hom. )

Consequence

PRKN
NM_004562.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.92

Publications

73 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=0.002216667).

BP6

Variant 6-162201165-C-T is Benign according to our data. Variant chr6-162201165-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3 link	c.500G>A	p.Ser167Asn	missense_variant	Exon 4 of 12	ENST00000366898.6	NP_004553.2	O60260-1X5DR79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6 link	c.500G>A	p.Ser167Asn	missense_variant	Exon 4 of 12	1	NM_004562.3	ENSP00000355865.1		O60260-1

Frequencies

GnomAD3 genomes

AF:

0.0570

AC:

8670

AN:

152134

Hom.:

679

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0744

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.0696

Gnomad FIN

AF:

0.00952

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0189

Gnomad OTH

AF:

0.0641

GnomAD2 exomes

AF:

0.0711

AC:

17873

AN:

251260

AF XY:

0.0647

show subpopulations

Gnomad AFR exome

AF:

0.0696

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.0425

Gnomad EAS exome

AF:

0.390

Gnomad FIN exome

AF:

0.00989

Gnomad NFE exome

AF:

0.0183

Gnomad OTH exome

AF:

0.0519

GnomAD4 exome

AF:

0.0359

AC:

52502

AN:

1461744

Hom.:

4198

Cov.:

AF XY:

0.0357

AC XY:

25984

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0695

AC:

2327

AN:

33470

American (AMR)

AF:

0.135

AC:

6057

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0420

AC:

1097

AN:

26136

East Asian (EAS)

AF:

0.392

AC:

15549

AN:

39692

South Asian (SAS)

AF:

0.0546

AC:

4710

AN:

86250

European-Finnish (FIN)

AF:

0.0102

AC:

543

AN:

53420

Middle Eastern (MID)

AF:

0.0180

AC:

104

AN:

5764

European-Non Finnish (NFE)

AF:

0.0171

AC:

18980

AN:

1111898

Other (OTH)

AF:

0.0519

AC:

3135

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2554

5107

7661

10214

12768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

998

1996

2994

3992

4990

<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:

0.0570

AC:

8671

AN:

152252

Hom.:

678

Cov.:

AF XY:

0.0600

AC XY:

4469

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0742

AC:

3083

AN:

41546

American (AMR)

AF:

0.104

AC:

1589

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3472

East Asian (EAS)

AF:

0.389

AC:

2005

AN:

5156

South Asian (SAS)

AF:

0.0690

AC:

333

AN:

4826

European-Finnish (FIN)

AF:

0.00952

AC:

101

AN:

10610

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0189

AC:

1285

AN:

68034

Other (OTH)

AF:

0.0658

AC:

139

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

366

733

1099

1466

1832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0386

Hom.:

1906

Bravo

AF:

0.0666

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.0783

AC:

345

ESP6500EA

AF:

0.0192

AC:

165

ExAC

AF:

0.0676

AC:

8206

Asia WGS

AF:

0.207

AC:

720

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0170

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

Jul 31, 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 24% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 22. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive juvenile Parkinson disease 2

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 06, 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. -

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

Benign:1

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 02, 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

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.59

PhyloP100

1.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0030

B;.;.

Vest4

0.14

MPC

0.053

ClinPred

0.0040

GERP RS

4.0

Varity_R

0.19

gMVP

0.16

Mutation Taster

=290/10

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