6-161975486-C-T

Variant names:

• chr6-161975486-C-T
• rs1789995
• NM_004562.3:c.619-2069G>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.619-2069G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 151,984 control chromosomes in the GnomAD database, including 10,693 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 0.37 (10693 hom., cov: 32)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.444
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.491 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.619-2069G>A		intron	N/A	NP_004553.2
	PRKN	NM_013987.3		c.535-2069G>A		intron	N/A	NP_054642.2
	PRKN	NM_013988.3		c.172-2069G>A		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.619-2069G>A		intron	N/A	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.535-2069G>A		intron	N/A	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.172-2069G>A		intron	N/A	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55977 AN: 151866 Hom.: 10697 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.368 AC: 55983 AN: 151984 Hom.: 10693 Cov.: 32 AF XY: 0.374 AC XY: 27796 AN XY: 74270

African (AFR) AF: 0.272 AC: 11255 AN: 41452

American (AMR) AF: 0.342 AC: 5217 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1317 AN: 3470

East Asian (EAS) AF: 0.414 AC: 2135 AN: 5154

South Asian (SAS) AF: 0.508 AC: 2444 AN: 4810

European-Finnish (FIN) AF: 0.438 AC: 4617 AN: 10548

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27668 AN: 67960

Other (OTH) AF: 0.363 AC: 766 AN: 2112

Alfa AF: 0.394 Hom.: 46775

Bravo AF: 0.353

Asia WGS AF: 0.424 AC: 1471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.73
PhyloP100		-0.44
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: rs1789995; hg19: chr6-162396518;