chr12-40309109-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198578.4(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. 12/21 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
NM_198578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.13

Publications

146 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant Parkinson disease 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRRK2 links:

ENSG00000258167 (HGNC:):

ENSG00000258167 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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.

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 rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4193G>A	p.Arg1398His	missense_variant	Exon 30 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.4193G>A	p.Arg1398His	missense_variant	Exon 30 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

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

GnomAD2 exomes

AF:

0.0848

AC:

21271

AN:

250816

AF XY:

0.0793

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 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

African (AFR)

AF:

0.142

AC:

4758

AN:

33426

American (AMR)

AF:

0.148

AC:

6590

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.0935

AC:

2441

AN:

26104

East Asian (EAS)

AF:

0.120

AC:

4764

AN:

39662

South Asian (SAS)

AF:

0.0394

AC:

3399

AN:

86212

European-Finnish (FIN)

AF:

0.0566

AC:

3020

AN:

53402

Middle Eastern (MID)

AF:

0.0506

AC:

290

AN:

5730

European-Non Finnish (NFE)

AF:

0.0687

AC:

76346

AN:

1111030

Other (OTH)

AF:

0.0783

AC:

4724

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

4806

9613

14419

19226

24032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0973

AC:

14780

AN:

151916

Hom.:

905

Cov.:

AF XY:

0.0970

AC XY:

7202

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.142

AC:

5861

AN:

41410

American (AMR)

AF:

0.152

AC:

2317

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3468

East Asian (EAS)

AF:

0.0997

AC:

516

AN:

5174

South Asian (SAS)

AF:

0.0415

AC:

200

AN:

4816

European-Finnish (FIN)

AF:

0.0551

AC:

580

AN:

10522

Middle Eastern (MID)

AF:

0.0890

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0693

AC:

4713

AN:

67972

Other (OTH)

AF:

0.0988

AC:

208

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

643

1287

1930

2574

3217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0786

Hom.:

2177

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

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 06, 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. -

Aug 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31487119, 29321258, 27013965, 28103901, 20186690, 23962496, 23913756, 20721913) -

not specified

Benign:2

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

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

- -

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

(source)

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

PhyloP100

3.1

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

Mutation Taster

=80/20

polymorphism (auto)

(source)

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

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chr12-40309109-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over