6-162727710-A-G

Position:

• chr6-162727710-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BS1_Supporting BS2_Supporting

The NM_004562.3(PRKN):​c.-42T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000607 in 1,556,414 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (3 hom.)
• Consequence: PRKN NM_004562.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.06

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]

PACRG (HGNC:19152): (parkin coregulated) This gene encodes a protein that is conserved across metazoans. In vertebrates, this gene is linked in a head-to-head arrangement with the adjacent parkin gene, which is associated with autosomal recessive juvenile Parkinson's disease. These genes are co-regulated in various tissues and they share a bi-directional promoter. Both genes are associated with susceptibility to leprosy. The parkin co-regulated gene protein forms a large molecular complex with chaperones, including heat shock proteins 70 and 90, and chaperonin components. This protein is also a component of Lewy bodies in Parkinson's disease patients, and it suppresses unfolded Pael receptor-induced neuronal cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000629 (883/1404188) while in subpopulation MID AF= 0.00863 (49/5680). AF 95% confidence interval is 0.0067. There are 3 homozygotes in gnomad4_exome. There are 525 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3	c.-42T>C		5_prime_UTR_variant	1/12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.-42T>C		5_prime_UTR_variant	1/12	1	NM_004562.3	ENSP00000355865	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00106 AC: 165 AN: 156042 Hom.: 1 AF XY: 0.00133 AC XY: 112 AN XY: 84380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000672

Gnomad ASJ exome AF: 0.000953

Gnomad EAS exome AF: 0.0000904

Gnomad SAS exome AF: 0.00354

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000726

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.000629 AC: 883 AN: 1404188 Hom.: 3 Cov.: 30 AF XY: 0.000756 AC XY: 525 AN XY: 694054

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000680

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.00317

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.000419

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152226 Hom.: 1 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74436

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000408

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.9
DANN	Benign	0.53

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: rs112850281; hg19: chr6-163148742;