rs3761863

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.7190T>C(p.Met2397Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,607,482 control chromosomes in the GnomAD database, including 342,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2397I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.62 ( 29240 hom., cov: 31)

Exomes 𝑓: 0.65 ( 312933 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.378

Publications

114 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
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

new If you want to explore the variant's impact on the transcript NM_198578.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=3.09017E-6).

BP6

Variant 12-40364850-T-C is Benign according to our data. Variant chr12-40364850-T-C is described in ClinVar as Benign. ClinVar VariationId is 308647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.662 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.7190T>C	p.Met2397Thr	missense	Exon 49 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.7190T>C	p.Met2397Thr	missense	Exon 49 of 51	ENSP00000298910.7	Q5S007
LRRK2	ENST00000430804.5	TSL:1	n.*3863T>C		non_coding_transcript_exon	Exon 28 of 30	ENSP00000410821.1	H7C3B6
LRRK2	ENST00000430804.5	TSL:1	n.*3863T>C		3_prime_UTR	Exon 28 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes

AF:

0.616

AC:

93446

AN:

151576

Hom.:

29223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.668

Gnomad AMR

AF:

0.585

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.749

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.667

Gnomad OTH

AF:

0.609

GnomAD2 exomes

AF:

0.617

AC:

153306

AN:

248412

AF XY:

0.623

show subpopulations

Gnomad AFR exome

AF:

0.526

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.468

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.665

Gnomad OTH exome

AF:

0.630

GnomAD4 exome

AF:

0.653

AC:

950317

AN:

1455788

Hom.:

312933

Cov.:

AF XY:

0.653

AC XY:

473248

AN XY:

724536

show subpopulations

African (AFR)

AF:

0.522

AC:

17385

AN:

33276

American (AMR)

AF:

0.508

AC:

22566

AN:

44458

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

15528

AN:

26002

East Asian (EAS)

AF:

0.462

AC:

18269

AN:

39566

South Asian (SAS)

AF:

0.630

AC:

54223

AN:

86048

European-Finnish (FIN)

AF:

0.742

AC:

39486

AN:

53228

Middle Eastern (MID)

AF:

0.528

AC:

3034

AN:

5742

European-Non Finnish (NFE)

AF:

0.669

AC:

741223

AN:

1107376

Other (OTH)

AF:

0.642

AC:

38603

AN:

60092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

14841

29682

44522

59363

74204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19058

38116

57174

76232

95290

<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:

0.616

AC:

93512

AN:

151694

Hom.:

29240

Cov.:

AF XY:

0.619

AC XY:

45906

AN XY:

74138

show subpopulations

African (AFR)

AF:

0.530

AC:

21946

AN:

41394

American (AMR)

AF:

0.585

AC:

8900

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2078

AN:

3462

East Asian (EAS)

AF:

0.469

AC:

2402

AN:

5126

South Asian (SAS)

AF:

0.618

AC:

2978

AN:

4816

European-Finnish (FIN)

AF:

0.749

AC:

7916

AN:

10568

Middle Eastern (MID)

AF:

0.551

AC:

162

AN:

294

European-Non Finnish (NFE)

AF:

0.667

AC:

45250

AN:

67812

Other (OTH)

AF:

0.605

AC:

1272

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1779

3558

5338

7117

8896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.639

Hom.:

102953

Bravo

AF:

0.598

Asia WGS

AF:

0.529

AC:

1839

AN:

3478

EpiCase

AF:

0.653

EpiControl

AF:

0.652

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Autosomal dominant Parkinson disease 8 (2)

Leprosy, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.22

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.14

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0000031

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

PhyloP100

0.38

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.53

REVEL

Benign

0.098

Sift

Benign

0.47

Sift4G

Benign

0.60

Varity_R

0.12

gMVP

0.54

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over