rs9365294

Variant names:

• chr6-161492631-G-C
• rs9365294
• NM_004562.3:c.1083+56223C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004562.3(PRKN):​c.1083+56223C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 152,168 control chromosomes in the GnomAD database, including 15,949 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (15949 hom., cov: 33)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.1083+56223C>G		intron_variant	Intron 9 of 11	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.1083+56223C>G		intron_variant	Intron 9 of 11	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 63015 AN: 152050 Hom.: 15953 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.459

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.414 AC: 63020 AN: 152168 Hom.: 15949 Cov.: 33 AF XY: 0.419 AC XY: 31143 AN XY: 74382

African (AFR) AF: 0.108 AC: 4502 AN: 41528

American (AMR) AF: 0.442 AC: 6752 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2302 AN: 3472

East Asian (EAS) AF: 0.495 AC: 2562 AN: 5172

South Asian (SAS) AF: 0.518 AC: 2501 AN: 4826

European-Finnish (FIN) AF: 0.550 AC: 5820 AN: 10582

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36785 AN: 67980

Other (OTH) AF: 0.459 AC: 972 AN: 2116

Alfa AF: 0.461 Hom.: 2280

Bravo AF: 0.389

Asia WGS AF: 0.493 AC: 1717 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.42
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism (auto)

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: rs9365294; hg19: chr6-161913663; COSMIC: COSV58264843;