rs10878307

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.2167A>G(p.Ile723Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,614,076 control chromosomes in the GnomAD database, including 3,947 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. I723M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 246 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3701 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.654

Publications

42 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=0.0012659132).

BP6

Variant 12-40278187-A-G is Benign according to our data. Variant chr12-40278187-A-G is described in ClinVar as Benign. ClinVar VariationId is 39146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.076 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.2167A>G	p.Ile723Val	missense	Exon 18 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.2167A>G	p.Ile723Val	missense	Exon 18 of 51	ENSP00000298910.7
LRRK2	ENST00000950031.1		c.2143A>G	p.Ile715Val	missense	Exon 18 of 51	ENSP00000620090.1
LRRK2	ENST00000680790.1		c.1912A>G	p.Ile638Val	missense	Exon 16 of 49	ENSP00000505335.1

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7417

AN:

152208

Hom.:

248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0123

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0425

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.00923

Gnomad SAS

AF:

0.0834

Gnomad FIN

AF:

0.0264

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.0700

Gnomad OTH

AF:

0.0698

GnomAD2 exomes

AF:

0.0585

AC:

14694

AN:

251266

AF XY:

0.0633

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.0351

Gnomad ASJ exome

AF:

0.143

Gnomad EAS exome

AF:

0.00397

Gnomad FIN exome

AF:

0.0275

Gnomad NFE exome

AF:

0.0720

Gnomad OTH exome

AF:

0.0700

GnomAD4 exome

AF:

0.0661

AC:

96605

AN:

1461750

Hom.:

3701

Cov.:

AF XY:

0.0674

AC XY:

48998

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0108

AC:

362

AN:

33478

American (AMR)

AF:

0.0374

AC:

1671

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3771

AN:

26130

East Asian (EAS)

AF:

0.0226

AC:

896

AN:

39654

South Asian (SAS)

AF:

0.0844

AC:

7276

AN:

86256

European-Finnish (FIN)

AF:

0.0305

AC:

1629

AN:

53414

Middle Eastern (MID)

AF:

0.141

AC:

812

AN:

5768

European-Non Finnish (NFE)

AF:

0.0685

AC:

76141

AN:

1111936

Other (OTH)

AF:

0.0670

AC:

4047

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

5391

10782

16172

21563

26954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2796

5592

8388

11184

13980

<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:

0.0486

AC:

7409

AN:

152326

Hom.:

246

Cov.:

AF XY:

0.0466

AC XY:

3469

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0123

AC:

513

AN:

41592

American (AMR)

AF:

0.0425

AC:

650

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

529

AN:

3472

East Asian (EAS)

AF:

0.00925

AC:

AN:

5188

South Asian (SAS)

AF:

0.0826

AC:

399

AN:

4828

European-Finnish (FIN)

AF:

0.0264

AC:

280

AN:

10622

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0700

AC:

4763

AN:

68004

Other (OTH)

AF:

0.0691

AC:

146

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

357

714

1070

1427

1784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0664

Hom.:

1590

Bravo

AF:

0.0479

TwinsUK

AF:

0.0688

AC:

255

ALSPAC

AF:

0.0714

AC:

275

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0714

AC:

614

ExAC

AF:

0.0592

AC:

7189

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

EpiCase

AF:

0.0798

EpiControl

AF:

0.0801

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant Parkinson disease 8 (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.027

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

0.65

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.020

REVEL

Benign

0.045

Sift

Benign

0.68

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.046

MPC

0.072

ClinPred

0.0030

GERP RS

-0.91

Varity_R

0.025

gMVP

0.079

Mutation Taster

=97/3

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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