rs137853060

Positions:

• chr6-161973403-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004562.3(PRKN):​c.633A>T​(p.Lys211Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,457,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K211I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.26

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a region_of_interest SYT11 binding 1 (size 34) in uniprot entity PRKN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004562.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 6-161973403-T-A is Pathogenic according to our data. Variant chr6-161973403-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-161973403-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3	c.633A>T	p.Lys211Asn	missense_variant	6/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6	c.633A>T	p.Lys211Asn	missense_variant	6/12	1	NM_004562.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251364 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135858

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1457332 Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14 AN XY: 725384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	May 09, 2023	ACMG criteria used to clasify this variant: PM1, PP3_MOD, PS3_SUP, PP2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2005	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRKN function (PMID: 25591737). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 7051). This missense change has been observed in individual(s) with early-onset Parkinson disease (PMID: 11222808, 15970950, 25833766). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs137853060, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 211 of the PRKN protein (p.Lys211Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationTaster	Benign	0.62	A;A;A;A;A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.97	D;.;.;.;.;.
Vest4		0.73
MutPred		0.85		Loss of methylation at K211 (P = 2e-04);.;.;.;.;Loss of methylation at K211 (P = 2e-04);
MVP		0.96
MPC		0.17
ClinPred		0.97	D
GERP RS		2.4
Varity_R		0.93
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs137853060; hg19: chr6-162394435;