rs746215864

Variant names:

• chr6-161548936-C-G
• rs746215864
• NM_004562.3:c.1001G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-161548936-C-G
• chr6-161548936-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004562.3(PRKN):​c.1001G>C​(p.Arg334Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R334C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26369643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.1001G>C	p.Arg334Pro	missense_variant	Exon 9 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.1001G>C	p.Arg334Pro	missense_variant	Exon 9 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111824

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	D;.;.;.;.;.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.056	N
LIST_S2	Uncertain	0.94	D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
PhyloP100		1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;N;N;.;N;N;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.13	T;T;T;.;T;T;T;.
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T
Polyphen		0.51	P;.;.;.;.;.;.;.
Vest4		0.48
MutPred		0.58		Gain of glycosylation at R334 (P = 0.0188);.;.;.;.;.;Gain of glycosylation at R334 (P = 0.0188);.;
MVP		0.92
MPC		0.22
ClinPred		0.78	D
GERP RS		3.0
Varity_R		0.94
gMVP		0.69
Mutation Taster		=73/27	polymorphism

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: rs746215864; hg19: chr6-161969968;