6-161350205-C-T

Variant names:

• chr6-161350205-C-T
• rs397514694
• NM_004562.3:c.1292G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_004562.3(PRKN):​c.1292G>A​(p.Cys431Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C431F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.91
• Publications: 45 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004562.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-161350205-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 50354.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.1292G>A	p.Cys431Tyr	missense_variant	Exon 12 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.1292G>A	p.Cys431Tyr	missense_variant	Exon 12 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460062 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726352

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53008

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110964

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.9
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-8.5	D;D;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.92
MutPred		0.86		Gain of phosphorylation at C431 (P = 0.0357);.;.;.;.;.;
MVP		1.0
MPC		0.45
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.88
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397514694; hg19: chr6-161771237;