chr6-161348405-G-A

Variant names:

• chr6-161348405-G-A
• rs16892481
• NM_004562.3:c.*1694C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004562.3(PRKN):​c.*1694C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 223,008 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (4 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.898
• Publications: 1 publications found

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]

PRKN Gene-Disease associations (from GenCC):

• autosomal recessive juvenile Parkinson disease 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine
• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1790/152226) while in subpopulation NFE AF = 0.0168 (1142/68004). AF 95% confidence interval is 0.016. There are 12 homozygotes in GnomAd4. There are 848 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	NM_004562.3	MANE Select	c.*1694C>T		3_prime_UTR	Exon 12 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.*1694C>T		3_prime_UTR	Exon 11 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.*1694C>T		3_prime_UTR	Exon 9 of 9	NP_054643.2	O60260-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.*1694C>T		3_prime_UTR	Exon 12 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000673871.1		n.*2086C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000501207.1	A0A669KBE3
	PRKN	ENST00000674006.1		n.2477C>T		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1791 AN: 152108 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.00910

GnomAD4 exome AF: 0.0122 AC: 862 AN: 70782 Hom.: 4 Cov.: 0 AF XY: 0.0123 AC XY: 401 AN XY: 32682

African (AFR) AF: 0.00406 AC: 13 AN: 3202

American (AMR) AF: 0.0127 AC: 26 AN: 2048

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 67 AN: 4516

East Asian (EAS) AF: 0.00106 AC: 11 AN: 10358

South Asian (SAS) AF: 0.00 AC: 0 AN: 596

European-Finnish (FIN) AF: 0.0200 AC: 1 AN: 50

Middle Eastern (MID) AF: 0.00234 AC: 1 AN: 428

European-Non Finnish (NFE) AF: 0.0149 AC: 650 AN: 43658

Other (OTH) AF: 0.0157 AC: 93 AN: 5926

GnomAD4 genome AF: 0.0118 AC: 1790 AN: 152226 Hom.: 12 Cov.: 32 AF XY: 0.0114 AC XY: 848 AN XY: 74404

African (AFR) AF: 0.00301 AC: 125 AN: 41536

American (AMR) AF: 0.0162 AC: 248 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0169 AC: 179 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1142 AN: 68004

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0164 Hom.: 5

Bravo AF: 0.0114

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive juvenile Parkinson disease 2 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.99
DANN	Benign	0.43
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs16892481; hg19: chr6-161769437;