rs7133914

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000298910.12(LRRK2):c.4193G>A(p.Arg1398His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,612,476 control chromosomes in the GnomAD database, including 5,310 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1398L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.097 ( 905 hom., cov: 32)

Exomes 𝑓: 0.073 ( 4405 hom. )

Consequence

LRRK2
ENST00000298910.12 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 3.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a mutagenesis_site Decreased kinase activity; when associated with G-1343. (size 0) in uniprot entity LRRK2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0027324557).

BP6

Variant 12-40309109-G-A is Benign according to our data. Variant chr12-40309109-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 39178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40309109-G-A is described in Lovd as [Likely_benign]. Variant chr12-40309109-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.147 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.4193G>A	p.Arg1398His	missense_variant	30/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.4193G>A	p.Arg1398His	missense_variant	30/51	1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes

AF:

0.0973

AC:

14774

AN:

151798

Hom.:

905

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.152

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.0417

Gnomad FIN

AF:

0.0551

Gnomad MID

AF:

0.0892

Gnomad NFE

AF:

0.0694

Gnomad OTH

AF:

0.101

GnomAD3 exomes

AF:

0.0848

AC:

21271

AN:

250816

Hom.:

1100

AF XY:

0.0793

AC XY:

10750

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.0933

Gnomad EAS exome

AF:

0.0985

Gnomad SAS exome

AF:

0.0400

Gnomad FIN exome

AF:

0.0554

Gnomad NFE exome

AF:

0.0727

Gnomad OTH exome

AF:

0.0765

GnomAD4 exome

AF:

0.0728

AC:

106332

AN:

1460560

Hom.:

4405

Cov.:

AF XY:

0.0713

AC XY:

51824

AN XY:

726604

show subpopulations

Gnomad4 AFR exome

AF:

0.142

Gnomad4 AMR exome

AF:

0.148

Gnomad4 ASJ exome

AF:

0.0935

Gnomad4 EAS exome

AF:

0.120

Gnomad4 SAS exome

AF:

0.0394

Gnomad4 FIN exome

AF:

0.0566

Gnomad4 NFE exome

AF:

0.0687

Gnomad4 OTH exome

AF:

0.0783

GnomAD4 genome

AF:

0.0973

AC:

14780

AN:

151916

Hom.:

905

Cov.:

AF XY:

0.0970

AC XY:

7202

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.142

Gnomad4 AMR

AF:

0.152

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.0997

Gnomad4 SAS

AF:

0.0415

Gnomad4 FIN

AF:

0.0551

Gnomad4 NFE

AF:

0.0693

Gnomad4 OTH

AF:

0.0988

Alfa

AF:

0.0736

Hom.:

965

Bravo

AF:

0.108

TwinsUK

AF:

0.0661

AC:

245

ALSPAC

AF:

0.0667

AC:

257

ESP6500AA

AF:

0.133

AC:

585

ESP6500EA

AF:

0.0724

AC:

623

ExAC

AF:

0.0840

AC:

10196

Asia WGS

AF:

0.0680

AC:

239

AN:

3478

EpiCase

AF:

0.0718

EpiControl

AF:

0.0682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 31487119, 29321258, 27013965, 28103901, 20186690, 23962496, 23913756, 20721913) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

-0.070

Eigen_PC

Benign

0.015

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.77

MutationTaster

Benign

0.058

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.37

Sift

Benign

0.10

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.086

MPC

0.21

ClinPred

0.040

GERP RS

2.8

Varity_R

0.19

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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