rs33995883

Positions:

Variant summary

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

The NM_198578.4(LRRK2):c.6241A>G(p.Asn2081Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0168 in 1,612,916 control chromosomes in the GnomAD database, including 379 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.017 ( 356 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.19

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00891602).

BP6

Variant 12-40346884-A-G is Benign according to our data. Variant chr12-40346884-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 39221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40346884-A-G is described in Lovd as [Benign]. Variant chr12-40346884-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.6241A>G	p.Asn2081Asp	missense_variant	42/51	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.6241A>G	p.Asn2081Asp	missense_variant	42/51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2067

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0524

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0325

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0176

AC:

4406

AN:

250168

Hom.:

AF XY:

0.0190

AC XY:

2572

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00956

Gnomad ASJ exome

AF:

0.0608

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.0322

Gnomad FIN exome

AF:

0.00315

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0171

AC:

25013

AN:

1460604

Hom.:

356

Cov.:

AF XY:

0.0178

AC XY:

12935

AN XY:

726576

show subpopulations

Gnomad4 AFR exome

AF:

0.00278

Gnomad4 AMR exome

AF:

0.0101

Gnomad4 ASJ exome

AF:

0.0552

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0338

Gnomad4 FIN exome

AF:

0.00414

Gnomad4 NFE exome

AF:

0.0163

Gnomad4 OTH exome

AF:

0.0218

GnomAD4 genome

AF:

0.0136

AC:

2066

AN:

152312

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1014

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00332

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.0524

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0329

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.0183

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0202

Hom.:

Bravo

AF:

0.0130

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0191

AC:

164

ExAC

AF:

0.0175

AC:

2118

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0263

EpiControl

AF:

0.0237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	This variant is associated with the following publications: (PMID: 32677286, 29795570, 29321258, 25378673) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.13

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.081

Sift4G

Uncertain

0.035

Polyphen

0.39

Vest4

0.19

MPC

1.9

ClinPred

0.015

GERP RS

5.6

Varity_R

0.46

gMVP

0.43

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