rs55830907

Variant names:

• chr6-161360169-G-A
• rs55830907
• NM_004562.3:c.1204C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004562.3(PRKN):​c.1204C>T​(p.Arg402Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,156 control chromosomes in the GnomAD database, including 12 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 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014354378).
• BP6: Variant 6-161360169-G-A is Benign according to our data. Variant chr6-161360169-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425402.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr6-161360169-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.1204C>T	p.Arg402Cys	missense_variant	Exon 11 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.1204C>T	p.Arg402Cys	missense_variant	Exon 11 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00194 AC: 487 AN: 251484 Hom.: 4 AF XY: 0.00205 AC XY: 279 AN XY: 135918

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00184 AC: 2697 AN: 1461850 Hom.: 9 Cov.: 31 AF XY: 0.00191 AC XY: 1390 AN XY: 727226

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74488

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00213

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00173 Hom.: 3

Bravo AF: 0.00172

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00200 AC: 243

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRKN: PM5, BS2 -

Autosomal recessive juvenile Parkinson disease 2 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

PRKN-related disorder Benign:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.
Eigen	Benign	0.015
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.96	D;D;D;D;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Uncertain	0.63	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.1	D;D;D;.;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.45
MVP		0.97
MPC		0.41
ClinPred		0.10	T
GERP RS		1.8
Varity_R		0.67
gMVP		0.85

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

Other links and lift over

dbSNP: rs55830907; hg19: chr6-161781201; COSMIC: COSV58208986;