rs2256408

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -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. 16/22 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 -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 id is 1169383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40225280-G-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	Exon 1 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.149G>A	p.Arg50His	missense_variant, splice_region_variant	Exon 1 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

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

GnomAD3 exomes

AF:

0.993

AC:

249243

AN:

251046

Hom.:

123794

AF XY:

0.995

AC XY:

135044

AN XY:

135766

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 SAS 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

Gnomad4 AFR exome

AF:

0.896

Gnomad4 AMR exome

AF:

0.996

Gnomad4 ASJ exome

AF:

1.00

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.994

GnomAD4 genome

AF:

0.972

AC:

148011

AN:

152268

Hom.:

72070

Cov.:

AF XY:

0.972

AC XY:

72363

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.902

Gnomad4 AMR

AF:

0.991

Gnomad4 ASJ

AF:

1.00

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.978

Alfa

AF:

0.995

Hom.:

144882

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0035

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

8.6e-7

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.26

.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.63

N;N

REVEL

Benign

0.029

Sift

Benign

1.0

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0

.;B

Vest4

0.014

MPC

0.11

ClinPred

0.0031

GERP RS

-1.3

Varity_R

0.025

gMVP

0.27

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

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