chr6-161494950-C-T

Variant names:

• chr6-161494950-C-T
• rs992421
• NM_004562.3:c.1083+53904G>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.1083+53904G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 152,014 control chromosomes in the GnomAD database, including 22,732 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 0.52 (22732 hom., cov: 32)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 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.1083+53904G>A		intron	N/A	NP_004553.2
	PRKN	NM_013987.3		c.999+53904G>A		intron	N/A	NP_054642.2
	PRKN	NM_013988.3		c.636+53904G>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.1083+53904G>A		intron	N/A	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.999+53904G>A		intron	N/A	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.636+53904G>A		intron	N/A	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78833 AN: 151896 Hom.: 22691 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.519 AC: 78927 AN: 152014 Hom.: 22732 Cov.: 32 AF XY: 0.508 AC XY: 37767 AN XY: 74292

African (AFR) AF: 0.774 AC: 32106 AN: 41484

American (AMR) AF: 0.416 AC: 6351 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1613 AN: 3464

East Asian (EAS) AF: 0.155 AC: 800 AN: 5176

South Asian (SAS) AF: 0.292 AC: 1402 AN: 4806

European-Finnish (FIN) AF: 0.390 AC: 4112 AN: 10538

Middle Eastern (MID) AF: 0.517 AC: 151 AN: 292

European-Non Finnish (NFE) AF: 0.456 AC: 30996 AN: 67962

Other (OTH) AF: 0.506 AC: 1068 AN: 2112

Alfa AF: 0.481 Hom.: 3197

Bravo AF: 0.535

Asia WGS AF: 0.279 AC: 968 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.16
DANN	Benign	0.64
PhyloP100		-1.1
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: rs992421; hg19: chr6-161915982; COSMIC: COSV58264915;