NM_004562.3:c.1330G>C

Variant names:

• chr6-161350167-C-G
• rs772592654
• NM_004562.3:c.1330G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004562.3(PRKN):​c.1330G>C​(p.Glu444Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32
• Publications: 8 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1330G>C	p.Glu444Gln	missense	Exon 12 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.1246G>C	p.Glu416Gln	missense	Exon 11 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.883G>C	p.Glu295Gln	missense	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.1330G>C	p.Glu444Gln	missense	Exon 12 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.1246G>C	p.Glu416Gln	missense	Exon 11 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.883G>C	p.Glu295Gln	missense	Exon 9 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249870 AF XY: 0.00000738

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461306 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726972

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74254

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.045	T
PhyloP100		3.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.45
Sift	Benign	0.056	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.20
MutPred		0.49		Gain of MoRF binding (P = 0.0637)
MVP		0.88
MPC		0.12
ClinPred		0.60	D
GERP RS		4.4
Varity_R		0.48
gMVP		0.76
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772592654; hg19: chr6-161771199; COSMIC: COSV100628057;