6-162727714-G-A

Variant names:

• chr6-162727714-G-A
• rs369389244
• NM_004562.3:c.-46C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004562.3(PRKN):​c.-46C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,551,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: PRKN NM_004562.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.145
• Publications: 0 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]

PACRG (HGNC:19152): (parkin coregulated) This gene encodes a protein that is conserved across metazoans. In vertebrates, this gene is linked in a head-to-head arrangement with the adjacent parkin gene, which is associated with autosomal recessive juvenile Parkinson's disease. These genes are co-regulated in various tissues and they share a bi-directional promoter. Both genes are associated with susceptibility to leprosy. The parkin co-regulated gene protein forms a large molecular complex with chaperones, including heat shock proteins 70 and 90, and chaperonin components. This protein is also a component of Lewy bodies in Parkinson's disease patients, and it suppresses unfolded Pael receptor-induced neuronal cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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.-46C>T		5_prime_UTR	Exon 1 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.-46C>T		5_prime_UTR	Exon 1 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.-46C>T		5_prime_UTR	Exon 1 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.-46C>T		5_prime_UTR	Exon 1 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.-46C>T		5_prime_UTR	Exon 1 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.-46C>T		5_prime_UTR	Exon 1 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000662 AC: 10 AN: 151100 AF XY: 0.0000612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.0000615 AC: 86 AN: 1398872 Hom.: 0 Cov.: 29 AF XY: 0.0000767 AC XY: 53 AN XY: 691004

African (AFR) AF: 0.0000318 AC: 1 AN: 31470

American (AMR) AF: 0.00 AC: 0 AN: 36300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 35850

South Asian (SAS) AF: 0.00 AC: 0 AN: 79504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.0000760 AC: 82 AN: 1078816

Other (OTH) AF: 0.0000517 AC: 3 AN: 57972

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74342

African (AFR) AF: 0.000121 AC: 5 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.000166

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive juvenile Parkinson disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		0.14
PromoterAI		-0.029	Neutral

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: rs369389244; hg19: chr6-163148746;