rs3761863

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198578.4(LRRK2):c.7190T>C(p.Met2397Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,607,482 control chromosomes in the GnomAD database, including 342,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 29240 hom., cov: 31)

Exomes 𝑓: 0.65 ( 312933 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.378

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:

LOC105369736 (HGNC:):

LOC105369736 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.09017E-6).

BP6

Variant 12-40364850-T-C is Benign according to our data. Variant chr12-40364850-T-C is described in ClinVar as [Benign]. Clinvar id is 308647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40364850-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.7190T>C	p.Met2397Thr	missense_variant	Exon 49 of 51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.7190T>C	p.Met2397Thr	missense_variant	Exon 49 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.616

AC:

93446

AN:

151576

Hom.:

29223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.668

Gnomad AMR

AF:

0.585

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.749

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.667

Gnomad OTH

AF:

0.609

GnomAD3 exomes

AF:

0.617

AC:

153306

AN:

248412

Hom.:

48382

AF XY:

0.623

AC XY:

83757

AN XY:

134394

show subpopulations

Gnomad AFR exome

AF:

0.526

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.468

Gnomad SAS exome

AF:

0.631

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.665

Gnomad OTH exome

AF:

0.630

GnomAD4 exome

AF:

0.653

AC:

950317

AN:

1455788

Hom.:

312933

Cov.:

AF XY:

0.653

AC XY:

473248

AN XY:

724536

show subpopulations

Gnomad4 AFR exome

AF:

0.522

Gnomad4 AMR exome

AF:

0.508

Gnomad4 ASJ exome

AF:

0.597

Gnomad4 EAS exome

AF:

0.462

Gnomad4 SAS exome

AF:

0.630

Gnomad4 FIN exome

AF:

0.742

Gnomad4 NFE exome

AF:

0.669

Gnomad4 OTH exome

AF:

0.642

GnomAD4 genome

AF:

0.616

AC:

93512

AN:

151694

Hom.:

29240

Cov.:

AF XY:

0.619

AC XY:

45906

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.530

Gnomad4 AMR

AF:

0.585

Gnomad4 ASJ

AF:

0.600

Gnomad4 EAS

AF:

0.469

Gnomad4 SAS

AF:

0.618

Gnomad4 FIN

AF:

0.749

Gnomad4 NFE

AF:

0.667

Gnomad4 OTH

AF:

0.605

Alfa

AF:

0.646

Hom.:

75724

Bravo

AF:

0.598

TwinsUK

AF:

0.650

AC:

2410

ALSPAC

AF:

0.665

AC:

2561

ESP6500AA

AF:

0.529

AC:

2328

ESP6500EA

AF:

0.655

AC:

5634

ExAC

AF:

0.617

AC:

74804

Asia WGS

AF:

0.529

AC:

1839

AN:

3478

EpiCase

AF:

0.653

EpiControl

AF:

0.652

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26844546, 25521227, 30917570, 25378673) -

Aug 04, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Parkinson disease 8

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leprosy, susceptibility to, 1

Other:1

Jun 10, 2022

Centro Dermatológico Federico Lleras Acosta, Hospital Universitario Centro Dermatológico Federico Lleras Acosta

Significance: confers sensitivity

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.22

DANN

Benign

0.13

DEOGEN2

Benign

0.14

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0000031

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.53

REVEL

Benign

0.098

Sift

Benign

0.47

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.028

MPC

0.23

ClinPred

0.00052

GERP RS

3.0

Varity_R

0.12

gMVP

0.54

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