rs34424986

Variant names:

• chr6-161785820-G-A
• rs34424986
• NM_004562.3:c.823C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-161785820-G-A
• chr6-161785820-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 13P and 3B. PS3 PP3 PP5_Very_Strong BP4 BS1_Supporting BS2_Supporting

The NM_004562.3(PRKN):​c.823C>T​(p.Arg275Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,016 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000461689: Functional studies showed that the variant protein forms intracellular aggregates, is unable to degrade substrates, and results in mitochondrial impairment, in particular reduction in ATP cellular levels (Cookson et al. 2003" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34 O:1
• Conservation: PhyloP100: 2.05
• Publications: 216 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000461689: Functional studies showed that the variant protein forms intracellular aggregates, is unable to degrade substrates, and results in mitochondrial impairment, in particular reduction in ATP cellular levels (Cookson et al. 2003; Sriram et al. 2005; Zanellati et al. 2015).; SCV002503704: The variant causes impaired localisation, mitochondrial ubiquitination, and protein formation in in vitro assays (PS3_Supporting; PMID: 14519684, 24647965, 25939424).; SCV002768549: Functional studies show that this variant causes an aggregation of mutant Parkin protein as large cytoplasmic and nuclear inclusions (Cookson, MR. et al. (2003)) and disrupts glutamatergic synaptic transmission in hippocampal neurons (Zhu, M. et al. (2018)).; SCV004241079: Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability with intracellular aggregates, impaired ubiquitination activity, and significantly decreased mitophagy, indicating a clear loss-of-function phenotype (e.g. Sriram_2005, Fiesel_2015, Yi_2019, Broadway_2022).; SCV000549208: Experimental studies have shown that this missense change affects PRKN function (PMID: 14519684, 16049031, 16714300, 20457763, 25939424).; SCV000843401: Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to altered protein localization in the formation of visible aggregates (PMID: 14519684, 16049031, 16714300).; SCV001823764: Published functional studies show the parkin protein with R275W accumulated around the nucleus in aggregations of misfolded protein, while wild type protein localized primarily to the cytoplasm and nucleus (Cookson et al., 2003); Published functional studies demonstrated that R275W inhibited differentiation of neural stem cells to astrocyte and neurons (Park et al., 2017).; SCV000731591: In vitro functional studies support that the p.Arg275Trw variant may impact protein function (Bertolin 2015, Fiesel 2015, Cookson 2003, Sriram 2005, and Zanellati 2015).; SCV004120437: an in vitro functional study found that this substitution decreased the solubility of the PRKN protein (Hampe et al. 2006. PubMed ID: 16714300).
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• PP5: Variant 6-161785820-G-A is Pathogenic according to our data. Variant chr6-161785820-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20339364). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0031 (4525/1461730) while in subpopulation NFE AF = 0.00375 (4171/1111924). AF 95% confidence interval is 0.00366. There are 9 homozygotes in GnomAdExome4. There are 2196 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 9 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	NM_004562.3	MANE Select	c.823C>T	p.Arg275Trp	missense	Exon 7 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.739C>T	p.Arg247Trp	missense	Exon 6 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.376C>T	p.Arg126Trp	missense	Exon 4 of 9	NP_054643.2	O60260-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.823C>T	p.Arg275Trp	missense	Exon 7 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.739C>T	p.Arg247Trp	missense	Exon 6 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.376C>T	p.Arg126Trp	missense	Exon 4 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152168 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00194 AC: 486 AN: 251096 AF XY: 0.00191

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00310 AC: 4525 AN: 1461730 Hom.: 9 Cov.: 32 AF XY: 0.00302 AC XY: 2196 AN XY: 727150

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86216

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00375 AC: 4171 AN: 1111924

Other (OTH) AF: 0.00265 AC: 160 AN: 60390

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152286 Hom.: 1 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74462

African (AFR) AF: 0.000794 AC: 33 AN: 41554

American (AMR) AF: 0.00294 AC: 45 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00269 Hom.: 6

Bravo AF: 0.00221

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00203 AC: 246

EpiCase AF: 0.00327

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Autosomal recessive juvenile Parkinson disease 2 (15)
11	-	-	not provided (11)
2	-	-	Lung cancer;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2 (2)
2	-	-	Young-onset Parkinson disease (2)
1	-	-	Lung carcinoma;C0919267:Ovarian neoplasm;C1843632:Leprosy, susceptibility to, 2;C1868675:Autosomal recessive juvenile Parkinson disease 2 (1)
1	-	-	Ovarian cancer (1)
1	-	-	Parkinson disease 12 (1)
1	-	-	PRKN-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.70	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.20	T
MetaSVM	Pathogenic	0.84	D
PhyloP100		2.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.97
MPC		0.37
ClinPred		0.058	T
GERP RS		4.9
Varity_R		0.90
gMVP		0.72
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs34424986; hg19: chr6-162206852; COSMIC: COSV58220231;