rs1801474

Positions:

• chr6-162201165-C-G
• chr6-162201165-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004562.3(PRKN):​c.500G>C​(p.Ser167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. S167N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a zinc_finger_region RING-type 0; atypical (size 84) in uniprot entity PRKN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004562.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23509455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.500G>C	p.Ser167Thr	missense_variant	4/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.500G>C	p.Ser167Thr	missense_variant	4/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.28	B;.;.
Vest4		0.25
MutPred		0.33		Loss of MoRF binding (P = 0.1204);Loss of MoRF binding (P = 0.1204);Loss of MoRF binding (P = 0.1204);
MVP		0.93
MPC		0.053
ClinPred		0.31	T
GERP RS		4.0
Varity_R		0.25
gMVP		0.22

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-162622197;