6-162201165-C-T

Position:

chr6-162201165-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/19 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:7O:1

Conservation

PhyloP100: 1.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a zinc_finger_region RING-type 0; atypical (size 84) in uniprot entity PRKN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004562.3

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 [Likely_benign]. Clinvar id is 41223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-162201165-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
PRKN	NM_004562.3 linkuse as main transcript	c.500G>A	p.Ser167Asn	missense_variant	4/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6 linkuse as main transcript	c.500G>A	p.Ser167Asn	missense_variant	4/12	1	NM_004562.3	P1	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

GnomAD3 exomes

AF:

0.0711

AC:

17873

AN:

251260

Hom.:

1970

AF XY:

0.0647

AC XY:

8788

AN XY:

135776

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 SAS exome

AF:

0.0559

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

Gnomad4 AFR exome

AF:

0.0695

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.0420

Gnomad4 EAS exome

AF:

0.392

Gnomad4 SAS exome

AF:

0.0546

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.0171

Gnomad4 OTH exome

AF:

0.0519

GnomAD4 genome

AF:

0.0570

AC:

8671

AN:

152252

Hom.:

678

Cov.:

AF XY:

0.0600

AC XY:

4469

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0742

Gnomad4 AMR

AF:

0.104

Gnomad4 ASJ

AF:

0.0366

Gnomad4 EAS

AF:

0.389

Gnomad4 SAS

AF:

0.0690

Gnomad4 FIN

AF:

0.00952

Gnomad4 NFE

AF:

0.0189

Gnomad4 OTH

AF:

0.0658

Alfa

AF:

0.0363

Hom.:

989

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:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive juvenile Parkinson disease 2

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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

MutationTaster

Benign

1.0

P;P;P;P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over