rs77428810

Positions:

chr12-40335031-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_198578.4(LRRK2):c.5822G>A(p.Arg1941His) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 4.58

Variant links:

Genes affected

LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]

LRRK2 links:

LRRK2 (HGNC:):

LRRK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32815164).

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.5822G>A	p.Arg1941His	missense_variant	40/51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.5822G>A	p.Arg1941His	missense_variant	40/51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251386

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000289

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:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000198

AC:

290

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000403

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:

0.000229

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000223

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Uncertain:4Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1941 of the LRRK2 protein (p.Arg1941His). This variant is present in population databases (rs77428810, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 16272164, 21885347, 33281709). ClinVar contains an entry for this variant (Variation ID: 39216). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRRK2 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LRRK2 function (PMID: 17447891, 17584768, 20642453, 35950872). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 29, 2023

Variant summary: LRRK2 c.5822G>A (p.Arg1941His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 (i.e., 35 heterozygotes) in 251386 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database (v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5822G>A has been reported in the literature in individuals affected with Parkinson Disease (e.g., Khan_2005, Ross_2011, Lubbe_2016, Muytemans_2020), however without strong evidence for causality (e.g., lack of co-segregation and co-occurrence data). These reports therefore do not provide unequivocal conclusions about association of the variant with Parkinson Disease 8, Autosomal Dominant. A co-occurrence with another pathogenic variant has been reported (LRRK2 c.6055G>A, p.Gly2019Ser; Lubbe_2016), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function with conflicting findings: two studies found the variant protein resulted in kinase activity similar to the wild-type (e.g., Luzon-Toro_2007, Nichols_2010), while another study found the variant resulted in approximately 33% of wild-type kinase activity (e.g., Jaleel_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17447891, 16272164, 27798102, 17584768, 20642453, 33281709, 21885347). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.11

Eigen

Benign

-0.091

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.024

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.32

REVEL

Benign

0.24

Sift

Benign

0.082

Sift4G

Benign

0.20

Polyphen

0.16

Vest4

0.40

MutPred

0.84

Loss of sheet (P = 0.1158);

MVP

0.83

MPC

1.5

ClinPred

0.12

GERP RS

4.8

Varity_R

0.15

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over