6-161977944-T-C

Variant names:

• chr6-161977944-T-C
• rs1789993
• NM_004562.3:c.619-4527A>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.619-4527A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 151,982 control chromosomes in the GnomAD database, including 18,210 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 0.49 (18210 hom., cov: 32)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.52 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.619-4527A>G		intron	N/A	NP_004553.2
	PRKN	NM_013987.3		c.535-4527A>G		intron	N/A	NP_054642.2
	PRKN	NM_013988.3		c.172-4527A>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.619-4527A>G		intron	N/A	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.535-4527A>G		intron	N/A	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.172-4527A>G		intron	N/A	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73924 AN: 151864 Hom.: 18186 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.475

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

GnomAD4 genome AF: 0.487 AC: 73991 AN: 151982 Hom.: 18210 Cov.: 32 AF XY: 0.491 AC XY: 36504 AN XY: 74290

African (AFR) AF: 0.505 AC: 20930 AN: 41426

American (AMR) AF: 0.418 AC: 6380 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1521 AN: 3470

East Asian (EAS) AF: 0.414 AC: 2141 AN: 5166

South Asian (SAS) AF: 0.537 AC: 2587 AN: 4816

European-Finnish (FIN) AF: 0.559 AC: 5895 AN: 10542

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32807 AN: 67976

Other (OTH) AF: 0.474 AC: 1002 AN: 2114

Alfa AF: 0.477 Hom.: 53920

Bravo AF: 0.473

Asia WGS AF: 0.460 AC: 1599 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.39
DANN	Benign	0.52
PhyloP100		-2.1
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: rs1789993; hg19: chr6-162398976;