rs11176013

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.4911A>G(p.Lys1637Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.558 in 1,608,610 control chromosomes in the GnomAD database, including 252,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 24558 hom., cov: 32)

Exomes 𝑓: 0.56 ( 227839 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 4.58

Publications

45 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 12-40320071-A-G is Benign according to our data. Variant chr12-40320071-A-G is described in ClinVar as Benign. ClinVar VariationId is 39199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4911A>G	p.Lys1637Lys	synonymous_variant	Exon 34 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.4911A>G	p.Lys1637Lys	synonymous_variant	Exon 34 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.567

AC:

86053

AN:

151726

Hom.:

24541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.588

Gnomad AMI

AF:

0.487

Gnomad AMR

AF:

0.630

Gnomad ASJ

AF:

0.553

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.696

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.545

Gnomad OTH

AF:

0.557

GnomAD2 exomes

AF:

0.576

AC:

143530

AN:

249074

AF XY:

0.576

show subpopulations

Gnomad AFR exome

AF:

0.586

Gnomad AMR exome

AF:

0.664

Gnomad ASJ exome

AF:

0.552

Gnomad EAS exome

AF:

0.476

Gnomad FIN exome

AF:

0.536

Gnomad NFE exome

AF:

0.544

Gnomad OTH exome

AF:

0.563

GnomAD4 exome

AF:

0.557

AC:

810800

AN:

1456766

Hom.:

227839

Cov.:

AF XY:

0.560

AC XY:

405490

AN XY:

724696

show subpopulations

African (AFR)

AF:

0.587

AC:

19509

AN:

33252

American (AMR)

AF:

0.659

AC:

29238

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14437

AN:

26044

East Asian (EAS)

AF:

0.479

AC:

18942

AN:

39572

South Asian (SAS)

AF:

0.688

AC:

58848

AN:

85532

European-Finnish (FIN)

AF:

0.540

AC:

28800

AN:

53348

Middle Eastern (MID)

AF:

0.502

AC:

2875

AN:

5728

European-Non Finnish (NFE)

AF:

0.545

AC:

604358

AN:

1108706

Other (OTH)

AF:

0.561

AC:

33793

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

18230

36460

54689

72919

91149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17118

34236

51354

68472

85590

<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:

0.567

AC:

86120

AN:

151844

Hom.:

24558

Cov.:

AF XY:

0.570

AC XY:

42262

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.588

AC:

24370

AN:

41426

American (AMR)

AF:

0.631

AC:

9614

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

1918

AN:

3466

East Asian (EAS)

AF:

0.482

AC:

2486

AN:

5162

South Asian (SAS)

AF:

0.695

AC:

3356

AN:

4828

European-Finnish (FIN)

AF:

0.531

AC:

5602

AN:

10542

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.545

AC:

37019

AN:

67876

Other (OTH)

AF:

0.554

AC:

1168

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1916

3831

5747

7662

9578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

736

1472

2208

2944

3680

<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:

0.563

Hom.:

23219

Bravo

AF:

0.571

Asia WGS

AF:

0.591

AC:

2047

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University 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

- -

Autosomal dominant Parkinson disease 8

Benign:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 13, 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 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

-0.58

CADD

Benign

8.3

(source)

DANN

Benign

0.62

PhyloP100

4.6

Mutation Taster

=76/24

polymorphism

(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