NM_004562.3:c.500G>A

Variant summary

Our verdict is Benign. Variant got -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. 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

17

Clinical Significance

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

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [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 rank MANE Protein UniProt
PRKNNM_004562.3 linkc.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
PRKNENST00000366898.6 linkc.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.:
32
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.:
32
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.:
32
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:
61
ALSPAC
AF:
0.0156
AC:
60
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
-
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

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Autosomal recessive juvenile Parkinson disease 2 Benign:1Other:1
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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

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
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.21
T;.;T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.59
T;T;T
MetaRNN
Benign
0.0022
T;T;T
MetaSVM
Benign
-0.59
T
PrimateAI
Benign
0.37
T
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
T
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.

Other links and lift over

dbSNP: rs1801474; hg19: chr6-162622197; COSMIC: COSV58202924; API