6-161350005-T-C

Variant names:

• chr6-161350005-T-C
• rs62637702
• NM_004562.3:c.*94A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004562.3(PRKN):​c.*94A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 684,804 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (50 hom., cov: 32)
  • Exomes 𝑓: 0.027 (178 hom.)
• Consequence: PRKN NM_004562.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.101
• Publications: 3 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: Laboratory for Molecular Medicine, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-161350005-T-C is Benign according to our data. Variant chr6-161350005-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 903814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0246 (3733/151710) while in subpopulation AFR AF = 0.0359 (1486/41430). AF 95% confidence interval is 0.0344. There are 50 homozygotes in GnomAd4. There are 1879 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.*94A>G		3_prime_UTR	Exon 12 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.*94A>G		3_prime_UTR	Exon 11 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.*94A>G		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.*94A>G		3_prime_UTR	Exon 12 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.*94A>G		3_prime_UTR	Exon 11 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.*94A>G		3_prime_UTR	Exon 9 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3726 AN: 151606 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0261

GnomAD4 exome AF: 0.0265 AC: 14136 AN: 533094 Hom.: 178 Cov.: 8 AF XY: 0.0270 AC XY: 7638 AN XY: 282608

African (AFR) AF: 0.0512 AC: 728 AN: 14206

American (AMR) AF: 0.0192 AC: 532 AN: 27756

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 588 AN: 16588

East Asian (EAS) AF: 0.000851 AC: 22 AN: 25856

South Asian (SAS) AF: 0.0424 AC: 2322 AN: 54756

European-Finnish (FIN) AF: 0.0411 AC: 1290 AN: 31354

Middle Eastern (MID) AF: 0.0416 AC: 115 AN: 2764

European-Non Finnish (NFE) AF: 0.0230 AC: 7661 AN: 332680

Other (OTH) AF: 0.0324 AC: 878 AN: 27134

GnomAD4 genome AF: 0.0246 AC: 3733 AN: 151710 Hom.: 50 Cov.: 32 AF XY: 0.0253 AC XY: 1879 AN XY: 74148

African (AFR) AF: 0.0359 AC: 1486 AN: 41430

American (AMR) AF: 0.0166 AC: 252 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3466

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5142

South Asian (SAS) AF: 0.0355 AC: 170 AN: 4792

European-Finnish (FIN) AF: 0.0419 AC: 440 AN: 10490

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1223 AN: 67878

Other (OTH) AF: 0.0253 AC: 53 AN: 2094

Alfa AF: 0.0251 Hom.: 17

Bravo AF: 0.0242

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive juvenile Parkinson disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.37
PhyloP100		0.10
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: rs62637702; hg19: chr6-161771037; COSMIC: COSV58234052; COSMIC: COSV58234052;