rs2256408

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.149G>A(p.Arg50His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,614,078 control chromosomes in the GnomAD database, including 799,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 72070 hom., cov: 31)

Exomes 𝑓: 1.0 ( 726959 hom. )

Consequence

LRRK2
NM_198578.4 missense, splice_region

Scores

Splicing: ADA: 0.00004042

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.216

Publications

49 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:

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=8.569986E-7).

BP6

Variant 12-40225280-G-A is Benign according to our data. Variant chr12-40225280-G-A is described in ClinVar as Benign. ClinVar VariationId is 1169383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.149G>A	p.Arg50His	missense splice_region	Exon 1 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.149G>A	p.Arg50His	missense splice_region	Exon 1 of 51	ENSP00000298910.7
LRRK2	ENST00000680790.1		c.149G>A	p.Arg50His	missense splice_region	Exon 1 of 49	ENSP00000505335.1
LRRK2	ENST00000343742.6	TSL:5	c.149G>A	p.Arg50His	missense splice_region	Exon 1 of 27	ENSP00000341930.2

Frequencies

GnomAD3 genomes

AF:

0.972

AC:

147895

AN:

152150

Hom.:

72012

Cov.:

show subpopulations

Gnomad AFR

AF:

0.902

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.978

GnomAD2 exomes

AF:

0.993

AC:

249243

AN:

251046

AF XY:

0.995

show subpopulations

Gnomad AFR exome

AF:

0.898

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.998

GnomAD4 exome

AF:

0.997

AC:

1457662

AN:

1461810

Hom.:

726959

Cov.:

AF XY:

0.998

AC XY:

725432

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.896

AC:

29987

AN:

33468

American (AMR)

AF:

0.996

AC:

44541

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26134

AN:

26134

East Asian (EAS)

AF:

1.00

AC:

39698

AN:

39698

South Asian (SAS)

AF:

1.00

AC:

86223

AN:

86242

European-Finnish (FIN)

AF:

1.00

AC:

53412

AN:

53412

Middle Eastern (MID)

AF:

0.997

AC:

5751

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111912

AN:

1111986

Other (OTH)

AF:

0.994

AC:

60004

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

236

472

709

945

1181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21668

43336

65004

86672

108340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.972

AC:

148011

AN:

152268

Hom.:

72070

Cov.:

AF XY:

0.972

AC XY:

72363

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.902

AC:

37482

AN:

41540

American (AMR)

AF:

0.991

AC:

15167

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5164

AN:

5164

South Asian (SAS)

AF:

1.00

AC:

4818

AN:

4820

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68019

AN:

68030

Other (OTH)

AF:

0.978

AC:

2067

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

192

385

577

770

962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.990

Hom.:

186933

Bravo

AF:

0.969

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.899

AC:

3959

ESP6500EA

AF:

1.00

AC:

8598

ExAC

AF:

0.991

AC:

120325

Asia WGS

AF:

0.995

AC:

3459

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Autosomal dominant Parkinson disease 8

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.023

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0035

LIST_S2

Benign

0.16

MetaRNN

Benign

8.6e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.26

PhyloP100

0.22

PrimateAI

Benign

0.40

PROVEAN

Benign

0.63

REVEL

Benign

0.029

Sift

Benign

1.0

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.014

MPC

0.11

ClinPred

0.0031

GERP RS

-1.3

PromoterAI

0.21

Neutral

(source)

Varity_R

0.025

gMVP

0.27

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over