6-161348078-C-T

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.*2021G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 186,890 control chromosomes in the GnomAD database, including 2,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (2035 hom., cov: 31)
  • Exomes 𝑓: 0.074 (145 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.914

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=-0.9).
• BP6: Variant 6-161348078-C-T is Benign according to our data. Variant chr6-161348078-C-T is described in ClinVar as [Benign]. Clinvar id is 355990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.*2021G>A		3_prime_UTR_variant	12/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.*2021G>A		3_prime_UTR_variant	12/12	1	NM_004562.3	P1
PRKN	ENST00000674006.1	n.2804G>A		non_coding_transcript_exon_variant	7/7
PRKN	ENST00000674436.1	n.3055G>A		non_coding_transcript_exon_variant	10/10
PRKN	ENST00000673871.1	c.*2413G>A		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19386 AN: 151874 Hom.: 2026 Cov.: 31

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0637

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0590

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0743 AC: 2592 AN: 34898 Hom.: 145 Cov.: 0 AF XY: 0.0755 AC XY: 1217 AN XY: 16126

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.0592

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.0663

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0551

Gnomad4 OTH exome AF: 0.0909

GnomAD4 genome AF: 0.128 AC: 19423 AN: 151992 Hom.: 2035 Cov.: 31 AF XY: 0.129 AC XY: 9614 AN XY: 74296

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.0634

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.0590

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.0567

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0756 Hom.: 200

Bravo AF: 0.133

Asia WGS AF: 0.179 AC: 624 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

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	-0.90
Cadd	Benign	0.45
Dann	Benign	0.66

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: rs1122470; hg19: chr6-161769110;