rs495991

Variant names:

• chr6-161534405-A-G
• rs495991
• NM_004562.3:c.1083+14449T>C

Variant summary

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

The ENST00000366898.6(PRKN):​c.1083+14449T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.839 in 152,142 control chromosomes in the GnomAD database, including 53,850 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 0.84 (53850 hom., cov: 32)
• Consequence: PRKN ENST00000366898.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 3 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366898.6. 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.1083+14449T>C		intron	N/A	NP_004553.2
	PRKN	NM_013987.3		c.999+14449T>C		intron	N/A	NP_054642.2
	PRKN	NM_013988.3		c.636+14449T>C		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.1083+14449T>C		intron	N/A	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.999+14449T>C		intron	N/A	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.636+14449T>C		intron	N/A	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127597 AN: 152024 Hom.: 53790 Cov.: 32

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.965

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.805

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.831

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

GnomAD4 genome AF: 0.839 AC: 127714 AN: 152142 Hom.: 53850 Cov.: 32 AF XY: 0.837 AC XY: 62215 AN XY: 74350

African (AFR) AF: 0.864 AC: 35876 AN: 41502

American (AMR) AF: 0.736 AC: 11252 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 3239 AN: 3472

East Asian (EAS) AF: 0.676 AC: 3492 AN: 5166

South Asian (SAS) AF: 0.806 AC: 3886 AN: 4820

European-Finnish (FIN) AF: 0.856 AC: 9040 AN: 10566

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 58031 AN: 68010

Other (OTH) AF: 0.833 AC: 1762 AN: 2114

Alfa AF: 0.844 Hom.: 49799

Bravo AF: 0.829

Asia WGS AF: 0.757 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.86
DANN	Benign	0.27
PhyloP100		-1.8
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: rs495991; hg19: chr6-161955437; COSMIC: COSV58265626;