rs149953814

Positions:

chr6-161350187-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_004562.3(PRKN):c.1310C>T(p.Pro437Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00274 in 1,613,282 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 8 hom. )

Consequence

PRKN
NM_004562.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 5.57

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030217081).

BP6

Variant 6-161350187-G-A is Benign according to our data. Variant chr6-161350187-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283504.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=6}.

BS2

High Homozygotes in GnomAdExome4 at 8 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3 linkuse as main transcript	c.1310C>T	p.Pro437Leu	missense_variant	12/12	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.1310C>T	p.Pro437Leu	missense_variant	12/12	1	NM_004562.3	ENSP00000355865	P1	O60260-1

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

322

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00343

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00159

AC:

396

AN:

249654

Hom.:

AF XY:

0.00152

AC XY:

206

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.000499

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.000898

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00255

Gnomad OTH exome

AF:

0.00313

GnomAD4 exome

AF:

0.00280

AC:

4093

AN:

1461040

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1930

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000245

Gnomad4 NFE exome

AF:

0.00336

Gnomad4 OTH exome

AF:

0.00345

GnomAD4 genome

AF:

0.00212

AC:

322

AN:

152242

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00343

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00226

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00138

AC:

167

EpiCase

AF:

0.00229

EpiControl

AF:

0.00232

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2024	Reported previously in an individual with early onset Parkinson disease who also harbored a second PRKN variant; however, parental studies were not performed (PMID: 15108293); Reported previously as pathogenic in an individual with Parkinson disease who also harbored a complex locus rearrangement presumed to be on the other allele; however, parental testing was not performed and detailed clinical information was not available (PMID: 32802956); Reported previously in the heterozygous state in individuals with Parkinson disease; however, it was also observed in unaffected controls (PMID: 24660942, 17262853, 24167364, 30363439, 30099245, 37750340); Published functional studies demonstrate a damaging effect showing that P437L significantly reduced binding ability and ubiquitination activity of parkin (PMID: 16049031, 29893854); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33751372, 33045815, 33845304, 29893854, 30363439, 30099245, 17187375, 19636047, 12629236, 26683220, 29887346, 28189762, 18546294, 24167364, 17262853, 30994895, 20643691, 34426522, 34434164, 34584092, 15266615, 38378758, 38767677, 36909283, 32802956, 15108293, 16049031, 24660942, 37750340) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 20, 2024

Variant summary: PRKN c.1310C>T (p.Pro437Leu) results in a non-conservative amino acid change located in the IBR domain (IPR002867) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 1613282 control chromosomes in the gnomAD database, including 9 homozygotes. c.1310C>T has been reported in the literature in individuals affected Parkinson disease/early onset PD (examples: Milanowski_2021, Castelo_2021, Lesage_2020, Pankratz_2009). These data do not allow any conclusion about variant significance. Functional studies have shown a damaging effect for P437L with reduced binding ability and ubiquitination activity of parkin (examples: Sriram_2005, Yi_2019) The following publications have been ascertained in the context of this evaluation (PMID: 30994895, 16049031, 33845304, 34434164, 33045815, 19636047). ClinVar contains an entry for this variant (Variation ID: 283504). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive juvenile Parkinson disease 2

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.;.;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

D;D;D;D;.;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.030

T;T;T;T;T;T

MetaSVM

Uncertain

-0.024

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

N;N;N;.;D;D

REVEL

Uncertain

0.64

Sift

Benign

0.055

T;T;D;.;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.55

MVP

0.95

MPC

0.36

ClinPred

0.028

GERP RS

5.3

Varity_R

0.53

gMVP

0.90

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