rs751037529

chr6-161785793-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Moderate

The NM_004562.3(PRKN):c.850G>C(p.Gly284Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.98

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_004562.3 (PRKN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest SYT11 binding 2 (size 36) in uniprot entity PRKN_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_004562.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 6-161785793-C-G is Pathogenic according to our data. Variant chr6-161785793-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 409266.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.850G>C	p.Gly284Arg	missense_variant	7/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.850G>C	p.Gly284Arg	missense_variant	7/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251102 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 08, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 284 of the PRKN protein (p.Gly284Arg). This variant is present in population databases (rs751037529, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive early-onset Parkinson disease (PMID: 12973932, 15642853, 18554280, 20399249, 24831986, 25045378, 27177722). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 409266). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKN protein function. Experimental studies have shown that this missense change affects PRKN function (PMID: 26161729). For these reasons, this variant has been classified as Pathogenic. -

Autism spectrum disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

This missense change has been observed in individuals with autosomal recessive early-onset Parkinson disease (PMID: 12973932, 15642853, 18554280, 20399249, 24831986, 25045378, 27177722). Experimental studies have shown that this missense change affected PRKN function (PMID: 26161729). In addition, the loss of the Prkn gene in mice resulted in autistic-like behaviors, accompanied with altered neuronal activity, abnormalities in synapse formation and synaptic molecular composition (PMID: 35789851). Disfunctional PARK2 may be associated with Autism Spectrum Disorder (ASD) (PMID: 36478299). In our study, a child diagnosed with ASD carries this PRKN rs751037529 mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.97
MutPred		0.86		Gain of loop (P = 0.1069);.;.;.;.;Gain of loop (P = 0.1069);
MVP		0.99
MPC		0.37
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.79

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: rs751037529; hg19: chr6-162206825;