6-161348404-C-T

Variant names:

• chr6-161348404-C-T
• rs77283740
• NM_004562.3:c.*1695G>A

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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.493
• 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 -20 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 VariationId is 355991.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 = 0.0159 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 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.*1695G>A		3_prime_UTR	Exon 12 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.*1695G>A		3_prime_UTR	Exon 11 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.*1695G>A		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.*1695G>A		3_prime_UTR	Exon 12 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000673871.1		n.*2087G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000501207.1	A0A669KBE3
	PRKN	ENST00000674006.1		n.2478G>A		non_coding_transcript_exon	Exon 7 of 7

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

African (AFR) AF: 0.0375 AC: 120 AN: 3200

American (AMR) AF: 0.0112 AC: 23 AN: 2054

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 81 AN: 4524

East Asian (EAS) AF: 0.00 AC: 0 AN: 10346

South Asian (SAS) AF: 0.0395 AC: 24 AN: 608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48

Middle Eastern (MID) AF: 0.0235 AC: 10 AN: 426

European-Non Finnish (NFE) AF: 0.00328 AC: 143 AN: 43652

Other (OTH) AF: 0.0123 AC: 73 AN: 5926

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

African (AFR) AF: 0.0437 AC: 1812 AN: 41502

American (AMR) AF: 0.0118 AC: 180 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

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

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 68000

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.00976 Hom.: 9

Bravo AF: 0.0182

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	-0.89
CADD	Benign	1.2
DANN	Benign	0.41
PhyloP100		-0.49
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: rs77283740; hg19: chr6-161769436;