6-161348404-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004562.3(PRKN):c.*1695G>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 0.013 in 222,950 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (3 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.493

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 6-161348404-C-T is Benign according to our data. Variant chr6-161348404-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 355991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0159 (2424/152166) while in subpopulation AFR AF= 0.0437 (1812/41502). AF 95% confidence interval is 0.042. There are 44 homozygotes in gnomad4. There are 1175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.*1695G>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.*1695G>A		3_prime_UTR_variant	12/12	1	NM_004562.3	P1
PRKN	ENST00000674006.1	n.2478G>A		non_coding_transcript_exon_variant	7/7
PRKN	ENST00000674436.1	n.2729G>A		non_coding_transcript_exon_variant	10/10
PRKN	ENST00000673871.1	c.*2087G>A		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2411 AN: 152048 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.00670 AC: 474 AN: 70784 Hom.: 3 Cov.: 0 AF XY: 0.00634 AC XY: 207 AN XY: 32672

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0395

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0159 AC: 2424 AN: 152166 Hom.: 44 Cov.: 32 AF XY: 0.0158 AC XY: 1175 AN XY: 74400

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00985 Hom.: 6

Bravo AF: 0.0182

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.89
Cadd	Benign	1.2
Dann	Benign	0.41

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: rs77283740; hg19: chr6-161769436;