NM_004562.3:c.155delA

Variant names:

• chr6-162443325-AT-A
• rs754809877
• NM_004562.3:c.155delA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004562.3(PRKN):​c.155delA​(p.Asn52MetfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,612,394 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: PRKN NM_004562.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 3.47
• Publications: 25 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-162443325-AT-A is Pathogenic according to our data. Variant chr6-162443325-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 536457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.155delA	p.Asn52MetfsTer29	frameshift	Exon 2 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.155delA	p.Asn52MetfsTer29	frameshift	Exon 2 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.155delA	p.Asn52MetfsTer24	frameshift	Exon 2 of 9	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.155delA	p.Asn52MetfsTer29	frameshift	Exon 2 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.155delA	p.Asn52MetfsTer29	frameshift	Exon 2 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.155delA	p.Asn52MetfsTer24	frameshift	Exon 2 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251320 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000277 AC: 405 AN: 1460246 Hom.: 0 Cov.: 33 AF XY: 0.000260 AC XY: 189 AN XY: 726416

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4426

European-Non Finnish (NFE) AF: 0.000305 AC: 339 AN: 1111998

Other (OTH) AF: 0.000133 AC: 8 AN: 60244

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74316

African (AFR) AF: 0.000121 AC: 5 AN: 41436

American (AMR) AF: 0.00170 AC: 26 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00239 AC: 5 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000374

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Autosomal recessive juvenile Parkinson disease 2 (8)
3	-	-	not provided (3)
2	-	-	Lung cancer;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs754809877; hg19: chr6-162864357;