6-162201272-A-G

Variant names:

• chr6-162201272-A-G
• rs4709583
• NM_004562.3:c.413-20T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004562.3(PRKN):​c.413-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.923 in 1,612,738 control chromosomes in the GnomAD database, including 687,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67602 hom., cov: 33)
  • Exomes 𝑓: 0.92 (620338 hom.)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.154
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-162201272-A-G is Benign according to our data. Variant chr6-162201272-A-G is described in ClinVar as Benign. ClinVar VariationId is 259433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.413-20T>C		intron_variant	Intron 3 of 11	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.413-20T>C		intron_variant	Intron 3 of 11	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.942 AC: 143326 AN: 152174 Hom.: 67547 Cov.: 33

Gnomad AFR AF: 0.983

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.928

GnomAD2 exomes AF: 0.934 AC: 234421 AN: 250952 AF XY: 0.930

Gnomad AFR exome AF: 0.984

Gnomad AMR exome AF: 0.964

Gnomad ASJ exome AF: 0.950

Gnomad EAS exome AF: 0.988

Gnomad FIN exome AF: 0.939

Gnomad NFE exome AF: 0.918

Gnomad OTH exome AF: 0.928

GnomAD4 exome AF: 0.921 AC: 1345623 AN: 1460446 Hom.: 620338 Cov.: 36 AF XY: 0.921 AC XY: 668906 AN XY: 726646

African (AFR) AF: 0.985 AC: 32947 AN: 33462

American (AMR) AF: 0.961 AC: 42959 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 24770 AN: 26128

East Asian (EAS) AF: 0.979 AC: 38873 AN: 39690

South Asian (SAS) AF: 0.896 AC: 77228 AN: 86238

European-Finnish (FIN) AF: 0.937 AC: 50020 AN: 53384

Middle Eastern (MID) AF: 0.930 AC: 5358 AN: 5762

European-Non Finnish (NFE) AF: 0.916 AC: 1017441 AN: 1110710

Other (OTH) AF: 0.928 AC: 56027 AN: 60350

GnomAD4 genome AF: 0.942 AC: 143441 AN: 152292 Hom.: 67602 Cov.: 33 AF XY: 0.942 AC XY: 70180 AN XY: 74462

African (AFR) AF: 0.983 AC: 40832 AN: 41550

American (AMR) AF: 0.942 AC: 14414 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3298 AN: 3472

East Asian (EAS) AF: 0.989 AC: 5119 AN: 5178

South Asian (SAS) AF: 0.901 AC: 4348 AN: 4824

European-Finnish (FIN) AF: 0.937 AC: 9942 AN: 10610

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.917 AC: 62393 AN: 68034

Other (OTH) AF: 0.929 AC: 1961 AN: 2112

Alfa AF: 0.938 Hom.: 57886

Bravo AF: 0.944

Asia WGS AF: 0.922 AC: 3207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 92. Only high quality variants are reported. -

not provided Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.5
DANN	Benign	0.63
PhyloP100		0.15
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: rs4709583; hg19: chr6-162622304;