NM_004562.3:c.1289G>A

Variant names:

• chr6-161350208-C-T
• rs191486604
• NM_004562.3:c.1289G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_004562.3(PRKN):​c.1289G>A​(p.Gly430Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000224 in 1,611,754 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000461686: Fiesel et al. (2015) demonstrated through molecular dynamic simulations that the p.Gly430Asp variant alters the active site of the enzyme through the introduction of a negative charge. In addition, the in vitro E3 ligase activity of the variant protein on a model substrate was reduced and mitochondrial relocalization was hampered in cells transfected with variant PARK2, as compared to wild type (Sriram et al. 2005" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G430S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.91
• Publications: 74 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000461686: Fiesel et al. (2015) demonstrated through molecular dynamic simulations that the p.Gly430Asp variant alters the active site of the enzyme through the introduction of a negative charge. In addition, the in vitro E3 ligase activity of the variant protein on a model substrate was reduced and mitochondrial relocalization was hampered in cells transfected with variant PARK2, as compared to wild type (Sriram et al. 2005; Okatsu et al. 2010; Fiesel et al. 2015).; SCV005900383: Functional studies with limited validation assaying cellular mitophagy are supportive of a damaging effect on protein function (PMID: 20098416).; SCV000946454: Experimental studies have shown that this missense change affects PRKN function (PMID: 16049031, 16339143, 20404107, 20604804, 20798600, 23751051).; SCV004773234: Functional studies showed that this variant could impact protein function (Sriram et al. 2005. PubMed ID: 16049031; Fiesel et al. 2015. PubMed ID: 25939424; Yi et al. 2019. PubMed ID: 30994895).; SCV004847939: "In vitro functional studies provide some evidence that the p.Gly430Asp variant may impact protein function (Sriram 2005)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004562.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-161350209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1120007.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 6-161350208-C-T is Pathogenic according to our data. Variant chr6-161350208-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 356016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1289G>A	p.Gly430Asp	missense	Exon 12 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.1205G>A	p.Gly402Asp	missense	Exon 11 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.842G>A	p.Gly281Asp	missense	Exon 9 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.1289G>A	p.Gly430Asp	missense	Exon 12 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.1205G>A	p.Gly402Asp	missense	Exon 11 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.842G>A	p.Gly281Asp	missense	Exon 9 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000603 AC: 15 AN: 248694 AF XY: 0.0000593

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000234 AC: 341 AN: 1459608 Hom.: 0 Cov.: 30 AF XY: 0.000234 AC XY: 170 AN XY: 726086

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000281 AC: 312 AN: 1110550

Other (OTH) AF: 0.000464 AC: 28 AN: 60286

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74312

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000176 Hom.: 1

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000989 AC: 12

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Autosomal recessive juvenile Parkinson disease 2 (3)
1	-	-	Lung cancer;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2 (1)
1	-	-	Ovarian cancer (1)
1	-	-	PRKN-related disorder (1)
1	-	-	Young-onset Parkinson disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.98
MPC		0.40
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.84
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: rs191486604; hg19: chr6-161771240;