rs577876

Variant names:

• chr6-161502123-A-G
• rs577876
• NM_004562.3:c.1083+46731T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-161502123-A-G
• chr6-161502123-A-T

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+46731T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,972 control chromosomes in the GnomAD database, including 11,710 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 0.38 (11710 hom., cov: 31)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	NM_004562.3	MANE Select	c.1083+46731T>C		intron	N/A	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.999+46731T>C		intron	N/A	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.636+46731T>C		intron	N/A	NP_054643.2	O60260-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.1083+46731T>C		intron	N/A	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.999+46731T>C		intron	N/A	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.636+46731T>C		intron	N/A	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58084 AN: 151854 Hom.: 11698 Cov.: 31

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.387

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

GnomAD4 genome AF: 0.383 AC: 58134 AN: 151972 Hom.: 11710 Cov.: 31 AF XY: 0.387 AC XY: 28737 AN XY: 74274

African (AFR) AF: 0.279 AC: 11552 AN: 41444

American (AMR) AF: 0.338 AC: 5162 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2066 AN: 3470

East Asian (EAS) AF: 0.536 AC: 2756 AN: 5142

South Asian (SAS) AF: 0.533 AC: 2567 AN: 4814

European-Finnish (FIN) AF: 0.428 AC: 4520 AN: 10560

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27910 AN: 67948

Other (OTH) AF: 0.390 AC: 824 AN: 2112

Alfa AF: 0.404 Hom.: 41095

Bravo AF: 0.368

Asia WGS AF: 0.496 AC: 1727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.44
PhyloP100		-0.38
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: rs577876; hg19: chr6-161923155;