rs10878307

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.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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 39146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40278187-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.076 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.2167A>G	p.Ile723Val	missense_variant	Exon 18 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.2167A>G	p.Ile723Val	missense_variant	Exon 18 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

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

GnomAD3 exomes

AF:

0.0585

AC:

14694

AN:

251266

Hom.:

637

AF XY:

0.0633

AC XY:

8590

AN XY:

135788

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 SAS exome

AF:

0.0848

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

Gnomad4 AFR exome

AF:

0.0108

Gnomad4 AMR exome

AF:

0.0374

Gnomad4 ASJ exome

AF:

0.144

Gnomad4 EAS exome

AF:

0.0226

Gnomad4 SAS exome

AF:

0.0844

Gnomad4 FIN exome

AF:

0.0305

Gnomad4 NFE exome

AF:

0.0685

Gnomad4 OTH exome

AF:

0.0670

GnomAD4 genome

AF:

0.0486

AC:

7409

AN:

152326

Hom.:

246

Cov.:

AF XY:

0.0466

AC XY:

3469

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0123

Gnomad4 AMR

AF:

0.0425

Gnomad4 ASJ

AF:

0.152

Gnomad4 EAS

AF:

0.00925

Gnomad4 SAS

AF:

0.0826

Gnomad4 FIN

AF:

0.0264

Gnomad4 NFE

AF:

0.0700

Gnomad4 OTH

AF:

0.0691

Alfa

AF:

0.0702

Hom.:

1155

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

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

DANN

Benign

0.61

DEOGEN2

Benign

0.027

.;T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

.;.;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.020

N;N;N

REVEL

Benign

0.045

Sift

Benign

0.68

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0010, 0.0

.;B;B

Vest4

0.046, 0.076

MPC

0.072

ClinPred

0.0030

GERP RS

-0.91

Varity_R

0.025

gMVP

0.079

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

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