NM_004562.3:c.689C>A

Variant names:

• chr6-161973347-G-T
• rs571490973
• NM_004562.3:c.689C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004562.3(PRKN):​c.689C>A​(p.Ala230Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A230V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30498463).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	NM_004562.3	MANE Select	c.689C>A	p.Ala230Glu	missense	Exon 6 of 12	NP_004553.2
	PRKN	NM_013987.3		c.605C>A	p.Ala202Glu	missense	Exon 5 of 11	NP_054642.2
	PRKN	NM_013988.3		c.242C>A	p.Ala81Glu	missense	Exon 3 of 9	NP_054643.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.689C>A	p.Ala230Glu	missense	Exon 6 of 12	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.605C>A	p.Ala202Glu	missense	Exon 5 of 11	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.242C>A	p.Ala81Glu	missense	Exon 3 of 9	ENSP00000355862.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.62	T
PhyloP100		5.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.25
Sift	Benign	0.070	T
Sift4G	Benign	0.072	T
Polyphen		0.0	B
Vest4		0.39
MutPred		0.40		Gain of solvent accessibility (P = 0.1185)
MVP		0.96
MPC		0.065
ClinPred		0.71	D
GERP RS		5.0
Varity_R		0.39
gMVP		0.23
Mutation Taster		=21/79	disease causing

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: rs571490973; hg19: chr6-162394379;