6-161348803-T-C

Variant names:

• chr6-161348803-T-C
• rs3734464
• NM_004562.3:c.*1296A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004562.3(PRKN):​c.*1296A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0816 in 210,028 control chromosomes in the GnomAD database, including 763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.082 (557 hom., cov: 32)
  • Exomes 𝑓: 0.080 (206 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.08
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-161348803-T-C is Benign according to our data. Variant chr6-161348803-T-C is described in CliVar as Benign. Clinvar id is 355998.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.*1296A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.*1296A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12525 AN: 152190 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.0772

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.0796 AC: 4596 AN: 57720 Hom.: 206 Cov.: 0 AF XY: 0.0807 AC XY: 2161 AN XY: 26794

African (AFR) AF: 0.0554 AC: 140 AN: 2526

American (AMR) AF: 0.0594 AC: 99 AN: 1668

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 412 AN: 3676

East Asian (EAS) AF: 0.0220 AC: 195 AN: 8870

South Asian (SAS) AF: 0.0784 AC: 40 AN: 510

European-Finnish (FIN) AF: 0.105 AC: 4 AN: 38

Middle Eastern (MID) AF: 0.0801 AC: 29 AN: 362

European-Non Finnish (NFE) AF: 0.0937 AC: 3307 AN: 35302

Other (OTH) AF: 0.0776 AC: 370 AN: 4768

GnomAD4 genome AF: 0.0823 AC: 12542 AN: 152308 Hom.: 557 Cov.: 32 AF XY: 0.0805 AC XY: 5996 AN XY: 74478

African (AFR) AF: 0.0603 AC: 2506 AN: 41578

American (AMR) AF: 0.0710 AC: 1086 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3470

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5180

South Asian (SAS) AF: 0.0769 AC: 371 AN: 4826

European-Finnish (FIN) AF: 0.0884 AC: 938 AN: 10614

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6846 AN: 68016

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.0928 Hom.: 1144

Bravo AF: 0.0776

Asia WGS AF: 0.0550 AC: 189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.064
DANN	Benign	0.36
PhyloP100		-2.1
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: rs3734464; hg19: chr6-161769835; COSMIC: COSV58210349; COSMIC: COSV58210349;