rs9458611

Variant names:

• chr6-162575231-C-T
• rs9458611
• NM_004562.3:c.8-131758G>A

Variant summary

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

The NM_004562.3(PRKN):​c.8-131758G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 152,024 control chromosomes in the GnomAD database, including 8,367 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 0.32 (8367 hom., cov: 32)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 5 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

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.8-131758G>A		intron	N/A	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.8-131758G>A		intron	N/A	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.8-131758G>A		intron	N/A	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.8-131758G>A		intron	N/A	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.8-131758G>A		intron	N/A	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.8-131758G>A		intron	N/A	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49021 AN: 151906 Hom.: 8359 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.323 AC: 49057 AN: 152024 Hom.: 8367 Cov.: 32 AF XY: 0.322 AC XY: 23892 AN XY: 74314

African (AFR) AF: 0.431 AC: 17865 AN: 41456

American (AMR) AF: 0.315 AC: 4811 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1090 AN: 3466

East Asian (EAS) AF: 0.215 AC: 1107 AN: 5156

South Asian (SAS) AF: 0.325 AC: 1566 AN: 4824

European-Finnish (FIN) AF: 0.241 AC: 2558 AN: 10598

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18953 AN: 67954

Other (OTH) AF: 0.325 AC: 687 AN: 2112

Alfa AF: 0.295 Hom.: 11636

Bravo AF: 0.331

Asia WGS AF: 0.297 AC: 1030 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.8
DANN	Benign	0.37
PhyloP100		-0.19
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: rs9458611; hg19: chr6-162996263;