rs9456735

Positions:

• chr6-162054135-T-A
• chr6-162054135-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004562.3(PRKN):​c.574A>T​(p.Met192Leu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78

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 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.574A>T	p.Met192Leu	missense_variant	5/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.574A>T	p.Met192Leu	missense_variant	5/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251356 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T;.;.;T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;.;D;T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.030	N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.055	T;T;T;D
Sift4G	Benign	0.084	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.27
MutPred		0.88		Loss of disorder (P = 0.1661);.;.;Loss of disorder (P = 0.1661);
MVP		0.89
MPC		0.31
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9456735; hg19: chr6-162475167;