rs199657839

chr6-161548937-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004562.3(PRKN):c.1000C>T(p.Arg334Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,024 control chromosomes in the GnomAD database, including 36 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. R334H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00071 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.316

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01292029).
• BP6: Variant 6-161548937-G-A is Benign according to our data. Variant chr6-161548937-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281504.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr6-161548937-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000709 (108/152246) while in subpopulation SAS AF= 0.021 (101/4816). AF 95% confidence interval is 0.0177. There are 2 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.1000C>T	p.Arg334Cys	missense_variant	9/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.1000C>T	p.Arg334Cys	missense_variant	9/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152128 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00241 AC: 605 AN: 251082 Hom.: 6 AF XY: 0.00339 AC XY: 461 AN XY: 135800

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00122 AC: 1783 AN: 1461778 Hom.: 34 Cov.: 31 AF XY: 0.00177 AC XY: 1284 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000675

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152246 Hom.: 2 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000273 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.00274 AC: 333

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). 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. -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Arg334Cys variant in PARK2 has been identified in 2 homozygous individuals and 1 heterozygous individual with Parkinson disease, segregated with disease in 2 relatives from 1 family (PMID: 10824074, 24082139, 22523156), but has also been identified in >1% of South Asian chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Of note, other variants of unknown significance in the same gene were identified in 2 homozygous individuals (PMID: 10824074). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Parkinson disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.048	N
LIST_S2	Pathogenic	0.97	D;D;D;D;.;D;D;D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.6	D;D;D;.;D;D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.028	D;D;D;.;D;D;D;.
Sift4G	Benign	0.075	T;T;T;T;T;T;T;T
Polyphen		0.98	D;.;.;.;.;.;.;.
Vest4		0.39
MVP		0.88
MPC		0.082
ClinPred		0.14	T
GERP RS		-5.8
Varity_R		0.24
gMVP		0.52

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: rs199657839; hg19: chr6-161969969;