NM_004562.3:c.734+75189T>C

Variant names:

• chr6-161898113-A-G
• rs9365344
• NM_004562.3:c.734+75189T>C

Variant summary

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

The NM_004562.3(PRKN):​c.734+75189T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 151,848 control chromosomes in the GnomAD database, including 12,037 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 0.39 (12037 hom., cov: 31)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.465
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.734+75189T>C		intron_variant	Intron 6 of 11	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.734+75189T>C		intron_variant	Intron 6 of 11	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59638 AN: 151732 Hom.: 12021 Cov.: 31

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.393 AC: 59690 AN: 151848 Hom.: 12037 Cov.: 31 AF XY: 0.394 AC XY: 29229 AN XY: 74214

African (AFR) AF: 0.321 AC: 13307 AN: 41420

American (AMR) AF: 0.453 AC: 6911 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1656 AN: 3470

East Asian (EAS) AF: 0.573 AC: 2962 AN: 5172

South Asian (SAS) AF: 0.368 AC: 1768 AN: 4806

European-Finnish (FIN) AF: 0.411 AC: 4315 AN: 10498

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27565 AN: 67924

Other (OTH) AF: 0.390 AC: 822 AN: 2106

Alfa AF: 0.407 Hom.: 17210

Bravo AF: 0.393

Asia WGS AF: 0.427 AC: 1488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.51
DANN	Benign	0.73
PhyloP100		-0.47
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: rs9365344; hg19: chr6-162319145; COSMIC: COSV58210857;