rs1801334

Positions:

chr6-161360193-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 -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 [Likely_benign]. Clinvar id is 41222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-161360193-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3 linkuse as main transcript	c.1180G>A	p.Asp394Asn	missense_variant	11/12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6 linkuse as main transcript	c.1180G>A	p.Asp394Asn	missense_variant	11/12	1	NM_004562.3	ENSP00000355865	P1	O60260-1

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

GnomAD3 exomes

AF:

0.0255

AC:

6405

AN:

251482

Hom.:

120

AF XY:

0.0255

AC XY:

3462

AN XY:

135918

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 SAS exome

AF:

0.00408

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

Gnomad4 AFR exome

AF:

0.00827

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.0388

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00371

Gnomad4 FIN exome

AF:

0.0334

Gnomad4 NFE exome

AF:

0.0408

Gnomad4 OTH exome

AF:

0.0311

GnomAD4 genome

AF:

0.0250

AC:

3807

AN:

152308

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1837

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00912

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0507

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.0334

Gnomad4 NFE

AF:

0.0378

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0348

Hom.:

185

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Autosomal recessive juvenile Parkinson disease 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, no assertion criteria provided	curation	GeneReviews	Apr 17, 2001	- -

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

Oct 01, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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

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

MutationTaster

Benign

0.99

N;N;N;N;N

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

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