6-161789902-T-C

Variant names:

• chr6-161789902-T-C
• rs3016557
• NM_004562.3:c.735-3994A>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.735-3994A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.866 in 151,820 control chromosomes in the GnomAD database, including 57,583 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 0.87 (57583 hom., cov: 33)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	NM_004562.3	MANE Select	c.735-3994A>G		intron	N/A	NP_004553.2
	PRKN	NM_013987.3		c.651-3994A>G		intron	N/A	NP_054642.2
	PRKN	NM_013988.3		c.288-3994A>G		intron	N/A	NP_054643.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.735-3994A>G		intron	N/A	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.651-3994A>G		intron	N/A	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.288-3994A>G		intron	N/A	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131357 AN: 151702 Hom.: 57561 Cov.: 33

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.925

Gnomad ASJ AF: 0.842

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.886

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

GnomAD4 genome AF: 0.866 AC: 131427 AN: 151820 Hom.: 57583 Cov.: 33 AF XY: 0.871 AC XY: 64688 AN XY: 74272

African (AFR) AF: 0.721 AC: 29635 AN: 41106

American (AMR) AF: 0.925 AC: 14140 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.842 AC: 2925 AN: 3472

East Asian (EAS) AF: 0.953 AC: 4927 AN: 5170

South Asian (SAS) AF: 0.909 AC: 4391 AN: 4830

European-Finnish (FIN) AF: 0.966 AC: 10260 AN: 10620

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.916 AC: 62330 AN: 68022

Other (OTH) AF: 0.887 AC: 1876 AN: 2114

Alfa AF: 0.900 Hom.: 33793

Bravo AF: 0.857

Asia WGS AF: 0.912 AC: 3170 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.63
PhyloP100		-0.34
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: rs3016557; hg19: chr6-162210934; COSMIC: COSV58210634;