rs1801334

chr6-161360193-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004562.3(PRKN):c.1180G>A(p.Asp394Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0341 in 1,613,134 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (64 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1086 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038829148).
• BP6: Variant 6-161360193-C-T is Benign according to our data. Variant chr6-161360193-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 41222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-161360193-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3807/152308) while in subpopulation NFE AF= 0.0378 (2571/68026). AF 95% confidence interval is 0.0366. There are 64 homozygotes in gnomad4. There are 1837 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.1180G>A	p.Asp394Asn	missense_variant	11/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.1180G>A	p.Asp394Asn	missense_variant	11/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3810 AN: 152190 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0255 AC: 6405 AN: 251482 Hom.: 120 AF XY: 0.0255 AC XY: 3462 AN XY: 135918

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0350 AC: 51172 AN: 1460826 Hom.: 1086 Cov.: 31 AF XY: 0.0341 AC XY: 24749 AN XY: 726818

Gnomad4 AFR exome AF: 0.00827

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0388

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00371

Gnomad4 FIN exome AF: 0.0334

Gnomad4 NFE exome AF: 0.0408

Gnomad4 OTH exome AF: 0.0311

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152308 Hom.: 64 Cov.: 32 AF XY: 0.0247 AC XY: 1837 AN XY: 74480

Gnomad4 AFR AF: 0.00912

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0334

Gnomad4 NFE AF: 0.0378

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0348 Hom.: 185

Bravo AF: 0.0239

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0443 AC: 381

ExAC AF: 0.0256 AC: 3108

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0381

EpiControl AF: 0.0372

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive juvenile Parkinson disease 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	curation	GeneReviews	Apr 17, 2001	- -

Lung cancer;C0919267:Neoplasm of ovary;C1868675:Autosomal recessive juvenile Parkinson disease 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.85	T;T;T;T;.;T
MetaRNN	Benign	0.0039	T;T;T;T;T;T
MetaSVM	Uncertain	0.0043	D
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D;D;D;.;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.023	D;D;T;.;T;T
Sift4G	Benign	0.071	T;T;T;T;T;T
Polyphen		0.56	P;.;.;.;.;.
Vest4		0.27
MPC		0.063
ClinPred		0.044	T
GERP RS		4.0
Varity_R		0.40
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs1801334; hg19: chr6-161781225; COSMIC: COSV58225382;