6-161827137-C-T

Variant names:

• chr6-161827137-C-T
• rs2022991
• NM_004562.3:c.735-41229G>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.735-41229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 152,022 control chromosomes in the GnomAD database, including 32,219 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 0.65 (32219 hom., cov: 32)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 8 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 (SAS) allele frequency at 95% confidence interval = 0.669 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.735-41229G>A		intron	N/A	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.651-41229G>A		intron	N/A	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.288-41229G>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.735-41229G>A		intron	N/A	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.651-41229G>A		intron	N/A	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.288-41229G>A		intron	N/A	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98677 AN: 151906 Hom.: 32200 Cov.: 32

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.649 AC: 98732 AN: 152022 Hom.: 32219 Cov.: 32 AF XY: 0.649 AC XY: 48178 AN XY: 74288

African (AFR) AF: 0.647 AC: 26810 AN: 41466

American (AMR) AF: 0.588 AC: 8977 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2397 AN: 3470

East Asian (EAS) AF: 0.547 AC: 2821 AN: 5156

South Asian (SAS) AF: 0.688 AC: 3317 AN: 4820

European-Finnish (FIN) AF: 0.653 AC: 6887 AN: 10544

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45389 AN: 67972

Other (OTH) AF: 0.664 AC: 1400 AN: 2110

Alfa AF: 0.658 Hom.: 140807

Bravo AF: 0.640

Asia WGS AF: 0.648 AC: 2249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.29
DANN	Benign	0.37
PhyloP100		-1.1
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: rs2022991; hg19: chr6-162248169; COSMIC: COSV58266875;