dbSNP rs149953814: PRKN:p.Pro437Leu (chr6-161350187-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P437A) has been classified as Uncertain significance.

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:7B:3

Conservation

PhyloP100: 5.57

Publications

42 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004562.3

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 VariationId is 283504.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKN	NM_004562.3	MANE Select	c.1310C>T	p.Pro437Leu	missense	Exon 12 of 12	NP_004553.2	O60260-1
PRKN	NM_013987.3		c.1226C>T	p.Pro409Leu	missense	Exon 11 of 11	NP_054642.2	O60260-2
PRKN	NM_013988.3		c.863C>T	p.Pro288Leu	missense	Exon 9 of 9	NP_054643.2	O60260-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKN	ENST00000366898.6	TSL:1 MANE Select	c.1310C>T	p.Pro437Leu	missense	Exon 12 of 12	ENSP00000355865.1	O60260-1
PRKN	ENST00000366897.5	TSL:1	c.1226C>T	p.Pro409Leu	missense	Exon 11 of 11	ENSP00000355863.1	O60260-2
PRKN	ENST00000366896.5	TSL:1	c.863C>T	p.Pro288Leu	missense	Exon 9 of 9	ENSP00000355862.1	O60260-6

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

GnomAD2 exomes

AF:

0.00159

AC:

396

AN:

249654

AF XY:

0.00152

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 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

African (AFR)

AF:

0.000329

AC:

AN:

33468

American (AMR)

AF:

0.00210

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.000245

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00336

AC:

3738

AN:

1111668

Other (OTH)

AF:

0.00345

AC:

208

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

182

364

547

729

911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.00212

AC:

322

AN:

152242

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

41540

American (AMR)

AF:

0.00379

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00343

AC:

233

AN:

68016

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00176

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal recessive juvenile Parkinson disease 2 (1)

Lung cancer;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2 (1)

not specified (1)

Parkinson disease 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.063

MetaRNN

Benign

0.030

MetaSVM

Uncertain

-0.024

PhyloP100

5.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.64

Sift

Benign

0.055

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.55

MVP

0.95

MPC

0.36

ClinPred

0.028

GERP RS

5.3

Varity_R

0.53

gMVP

0.90

Mutation Taster

=3/97

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over