NM_004562.3:c.500G>A

Variant names:

• chr6-162201165-C-T
• rs1801474
• NM_004562.3:c.500G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.92
• Publications: 73 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 41223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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
PRKN	NM_004562.3	c.500G>A	p.Ser167Asn	missense_variant	Exon 4 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.500G>A	p.Ser167Asn	missense_variant	Exon 4 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8670 AN: 152134 Hom.: 679 Cov.: 32

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

GnomAD2 exomes AF: 0.0711 AC: 17873 AN: 251260 AF XY: 0.0647

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 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

African (AFR) AF: 0.0695 AC: 2327 AN: 33470

American (AMR) AF: 0.135 AC: 6057 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0420 AC: 1097 AN: 26136

East Asian (EAS) AF: 0.392 AC: 15549 AN: 39692

South Asian (SAS) AF: 0.0546 AC: 4710 AN: 86250

European-Finnish (FIN) AF: 0.0102 AC: 543 AN: 53420

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5764

European-Non Finnish (NFE) AF: 0.0171 AC: 18980 AN: 1111898

Other (OTH) AF: 0.0519 AC: 3135 AN: 60390

GnomAD4 genome AF: 0.0570 AC: 8671 AN: 152252 Hom.: 678 Cov.: 32 AF XY: 0.0600 AC XY: 4469 AN XY: 74426

African (AFR) AF: 0.0742 AC: 3083 AN: 41546

American (AMR) AF: 0.104 AC: 1589 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3472

East Asian (EAS) AF: 0.389 AC: 2005 AN: 5156

South Asian (SAS) AF: 0.0690 AC: 333 AN: 4826

European-Finnish (FIN) AF: 0.00952 AC: 101 AN: 10610

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0189 AC: 1285 AN: 68034

Other (OTH) AF: 0.0658 AC: 139 AN: 2114

Alfa AF: 0.0386 Hom.: 1906

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. -

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
PhyloP100		1.9
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
Mutation Taster		=290/10	polymorphism (auto)

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

Other links and lift over

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