rs138920699

Variant names:

• chr6-161569369-G-A
• rs138920699
• NM_004562.3:c.919C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BS2_Supporting

The NM_004562.3(PRKN):​c.919C>T​(p.Leu307Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000441 in 1,613,550 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: PRKN NM_004562.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.55
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 6-161569369-G-A is Benign according to our data. Variant chr6-161569369-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 444707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.919C>T	p.Leu307Leu	synonymous	Exon 8 of 12	NP_004553.2
	PRKN	NM_013987.3		c.835C>T	p.Leu279Leu	synonymous	Exon 7 of 11	NP_054642.2
	PRKN	NM_013988.3		c.472C>T	p.Leu158Leu	synonymous	Exon 5 of 9	NP_054643.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.919C>T	p.Leu307Leu	synonymous	Exon 8 of 12	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.835C>T	p.Leu279Leu	synonymous	Exon 7 of 11	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.472C>T	p.Leu158Leu	synonymous	Exon 5 of 9	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000545 AC: 137 AN: 251448 AF XY: 0.000545

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1461348 Hom.: 3 Cov.: 31 AF XY: 0.000450 AC XY: 327 AN XY: 727004

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000468 AC: 520 AN: 1111556

Other (OTH) AF: 0.000315 AC: 19 AN: 60382

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000713 AC XY: 53 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000887 Hom.: 1

Bravo AF: 0.000393

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Autosomal recessive juvenile Parkinson disease 2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		6.6
PromoterAI		-0.029	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138920699; hg19: chr6-161990401;