6-161347619-G-T

Position:

• chr6-161347619-G-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.*2480C>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 0.372 in 110,216 control chromosomes in the GnomAD database, including 7,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (7580 hom., cov: 22)
  • 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: -0.253

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 6-161347619-G-T is Benign according to our data. Variant chr6-161347619-G-T is described in ClinVar as [Benign]. Clinvar id is 355981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.*2480C>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.*2480C>A		3_prime_UTR_variant	12/12	1	NM_004562.3	P1
PRKN	ENST00000674006.1	n.3263C>A		non_coding_transcript_exon_variant	7/7
PRKN	ENST00000674436.1	n.3514C>A		non_coding_transcript_exon_variant	10/10
PRKN	ENST00000673871.1	c.*2872C>A		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.372 AC: 40958 AN: 110210 Hom.: 7570 Cov.: 22

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.0853

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.319

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.356

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 14

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.372 AC: 40980 AN: 110216 Hom.: 7580 Cov.: 22 AF XY: 0.367 AC XY: 19283 AN XY: 52496

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.0851

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.362

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	0.19
DANN	Benign	0.78

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: rs68121389; hg19: chr6-161768651; COSMIC: COSV58210346; COSMIC: COSV58210346;