Variant chr6-162443325-AT-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 3.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-162443325-AT-A is Pathogenic according to our data. Variant chr6-162443325-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 536457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-162443325-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3 link	c.155delA	p.Asn52MetfsTer29	frameshift_variant	Exon 2 of 12	ENST00000366898.6	NP_004553.2	O60260-1X5DR79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6 link	c.155delA	p.Asn52MetfsTer29	frameshift_variant	Exon 2 of 12	1	NM_004562.3	ENSP00000355865.1		O60260-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000263

AC:

AN:

251320

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135828

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

726416

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000305

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000289

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000374

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2

Pathogenic:8

Jul 27, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2024

Genetics Department, Catlab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155del variant in the PRKN gene is a loss of function variant predicted to undergo nonsense mediated decay and loss of function variants have been described as a causing mechanism for the gene (PVS1). The variant has a low frequency in gnomAD 4.1 (AF= 0.0002785) (PM2) and has been previously reported in homozygous and heterozygous state in multiple independent Parkinson patients (PMID: 10072423, 16769863, 27206984, 30537300, 20558392) (PM3_Very strong). Finally, functional studies using patient derived material suggest a deleterious effect of the variant (PS3_Supporting). With all the available evidence, the variant is classified as pathogenic. -

Nov 13, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM3_VSTR,PM2_SUP -

Oct 04, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PARK2 c.155delA (p.Asn52MetfsTer29) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Asn52MetfsTer29 variant, which is also referred to in the literature as c.255delA, was reported in 24 individuals with juvenile Parkinson disease, including ten in a homozygous state, seven in a compound heterozygous state, and seven in a heterozygous state where zygosity is not noted (Abbas et al. 1999; Lucking et al. 2000; Hoenicka et al. 2002; Munoz et al. 2002; Marder et al. 2010; Guerrero Camacho et al. 2012). The p.Asn52MetfsTer29 variant was also found in a heterozygous state in seven unaffected relatives (Hoenicka et al. 2002). The p.Asn52MetfsTer29 variant was reported in two of 283 controls and is reported at a frequency of 0.001123 in the Latino population of the Exome Aggregation Consortium. Due to the presence of this variant in a large number of cases, and the potential functional impact of frameshift variants, the p.Asn52MetfsTer29 variant is classified as pathogenic for juvenile Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 20, 2023

Human Genetics Laboratory, State University of Rio de Janeiro

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 05, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:3

Mar 23, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn52Metfs*29) in the PRKN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRKN are known to be pathogenic (PMID: 10072423, 20301651, 22956510). This variant is present in population databases (rs754809877, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Parkinson disease (PMID: 10072423, 16769863, 18211709, 27206984, 30537300). It has also been observed to segregate with disease in related individuals. This variant is also known as 255delA, c.154delA, N52fsX80, Asn52/Stop81, and N52/STOP80. ClinVar contains an entry for this variant (Variation ID: 536457). For these reasons, this variant has been classified as Pathogenic. -

Nov 19, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. -

Lung cancer;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2

Pathogenic:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over