NM_004562.3:c.838G>C

Variant names:

• chr6-161785805-C-G
• rs72480422
• NM_004562.3:c.838G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004562.3(PRKN):​c.838G>C​(p.Asp280His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D280N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_004562.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3571778).

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.838G>C	p.Asp280His	missense	Exon 7 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.754G>C	p.Asp252His	missense	Exon 6 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.391G>C	p.Asp131His	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.838G>C	p.Asp280His	missense	Exon 7 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.754G>C	p.Asp252His	missense	Exon 6 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.391G>C	p.Asp131His	missense	Exon 4 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.71
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.10	T
PhyloP100		3.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.50	T
Sift4G	Benign	0.46	T
Polyphen		0.22	B
Vest4		0.48
MutPred		0.66		Gain of catalytic residue at D280 (P = 0.2929)
MVP		0.96
MPC		0.39
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.59
Mutation Taster		=50/50

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: rs72480422; hg19: chr6-162206837;