6-161347607-T-C

Position:

• chr6-161347607-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004562.3(PRKN):​c.*2492A>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 0.0467 in 142,496 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (261 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.456

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-161347607-T-C is Benign according to our data. Variant chr6-161347607-T-C is described in ClinVar as [Benign]. Clinvar id is 355980.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3	c.*2492A>G		3_prime_UTR_variant	12/12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.*2492A>G		3_prime_UTR_variant	12/12	1	NM_004562.3	ENSP00000355865	P1
PRKN	ENST00000674006.1	n.3275A>G		non_coding_transcript_exon_variant	7/7
PRKN	ENST00000674436.1	n.3526A>G		non_coding_transcript_exon_variant	10/10
PRKN	ENST00000673871.1	c.*2884A>G		3_prime_UTR_variant, NMD_transcript_variant	12/12			ENSP00000501207

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 6663 AN: 142440 Hom.: 261 Cov.: 31

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0210

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0327

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0562

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 174 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 146

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0467 AC: 6655 AN: 142496 Hom.: 261 Cov.: 31 AF XY: 0.0493 AC XY: 3415 AN XY: 69204

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0544

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0547

Gnomad4 OTH AF: 0.0584

Alfa AF: 0.0488 Hom.: 35

Bravo AF: 0.0418

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.89
CADD	Benign	1.1
DANN	Benign	0.60

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: rs117341007; hg19: chr6-161768639; COSMIC: COSV58221389; COSMIC: COSV58221389;