chr6-161350005-T-C

Position:

• chr6-161350005-T-C

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.*94A>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 0.0261 in 684,804 control chromosomes in the GnomAD database, including 228 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 (50 hom., cov: 32)
  • Exomes 𝑓: 0.027 (178 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.101

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 (BayesDel_noAF=-0.87).
• BP6: Variant 6-161350005-T-C is Benign according to our data. Variant chr6-161350005-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 903814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0246 (3733/151710) while in subpopulation AFR AF= 0.0359 (1486/41430). AF 95% confidence interval is 0.0344. There are 50 homozygotes in gnomad4. There are 1879 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3	c.*94A>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.*94A>G		3_prime_UTR_variant	12/12	1	NM_004562.3	ENSP00000355865	P1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3726 AN: 151606 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0261

GnomAD4 exome AF: 0.0265 AC: 14136 AN: 533094 Hom.: 178 Cov.: 8 AF XY: 0.0270 AC XY: 7638 AN XY: 282608

Gnomad4 AFR exome AF: 0.0512

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.000851

Gnomad4 SAS exome AF: 0.0424

Gnomad4 FIN exome AF: 0.0411

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0324

GnomAD4 genome AF: 0.0246 AC: 3733 AN: 151710 Hom.: 50 Cov.: 32 AF XY: 0.0253 AC XY: 1879 AN XY: 74148

Gnomad4 AFR AF: 0.0359

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.000972

Gnomad4 SAS AF: 0.0355

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0253

Alfa AF: 0.0190 Hom.: 7

Bravo AF: 0.0242

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2019	This variant is associated with the following publications: (PMID: 23275044) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive juvenile Parkinson disease 2 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.37

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: rs62637702; hg19: chr6-161771037; COSMIC: COSV58234052; COSMIC: COSV58234052;