rs10878405

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_198578.4(LRRK2):c.6324G>A(p.Glu2108Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,607,610 control chromosomes in the GnomAD database, including 80,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6173 hom., cov: 33)

Exomes 𝑓: 0.31 ( 73852 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 3.27

Publications

32 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:

ENSG00000258167 (HGNC:):

ENSG00000258167 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 12-40348452-G-A is Benign according to our data. Variant chr12-40348452-G-A is described in ClinVar as Benign. ClinVar VariationId is 39222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.6324G>A	p.Glu2108Glu	synonymous_variant	Exon 43 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.6324G>A	p.Glu2108Glu	synonymous_variant	Exon 43 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41286

AN:

151872

Hom.:

6171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.194

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.341

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.264

GnomAD2 exomes

AF:

0.302

AC:

75665

AN:

250916

AF XY:

0.309

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.208

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.384

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.308

GnomAD4 exome

AF:

0.313

AC:

456015

AN:

1455620

Hom.:

73852

Cov.:

AF XY:

0.315

AC XY:

228474

AN XY:

724384

show subpopulations

African (AFR)

AF:

0.142

AC:

4731

AN:

33398

American (AMR)

AF:

0.214

AC:

9577

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

7145

AN:

26084

East Asian (EAS)

AF:

0.320

AC:

12635

AN:

39538

South Asian (SAS)

AF:

0.360

AC:

30953

AN:

86062

European-Finnish (FIN)

AF:

0.381

AC:

20324

AN:

53378

Middle Eastern (MID)

AF:

0.238

AC:

1334

AN:

5600

European-Non Finnish (NFE)

AF:

0.317

AC:

350975

AN:

1106696

Other (OTH)

AF:

0.305

AC:

18341

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

14438

28875

43313

57750

72188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11238

22476

33714

44952

56190

<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:

0.272

AC:

41305

AN:

151990

Hom.:

6173

Cov.:

AF XY:

0.278

AC XY:

20613

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.148

AC:

6120

AN:

41462

American (AMR)

AF:

0.259

AC:

3959

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

916

AN:

3472

East Asian (EAS)

AF:

0.341

AC:

1766

AN:

5180

South Asian (SAS)

AF:

0.368

AC:

1778

AN:

4826

European-Finnish (FIN)

AF:

0.377

AC:

3962

AN:

10502

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22001

AN:

67968

Other (OTH)

AF:

0.266

AC:

562

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1514

3028

4541

6055

7569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

440

880

1320

1760

2200

<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:

0.293

Hom.:

12129

Bravo

AF:

0.253

Asia WGS

AF:

0.337

AC:

1167

AN:

3472

EpiCase

AF:

0.305

EpiControl

AF:

0.310

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

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. -

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.6

(source)

DANN

Benign

0.56

PhyloP100

3.3

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over