rs11175964

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198578.4(LRRK2):c.4269G>A(p.Lys1423Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,646 control chromosomes in the GnomAD database, including 4,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 391 hom., cov: 32)

Exomes 𝑓: 0.069 ( 3898 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.22

Publications

51 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-40309185-G-A is Benign according to our data. Variant chr12-40309185-G-A is described in ClinVar as Benign. ClinVar VariationId is 39181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4269G>A	p.Lys1423Lys	synonymous_variant	Exon 30 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.4269G>A	p.Lys1423Lys	synonymous_variant	Exon 30 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0603

AC:

9160

AN:

151992

Hom.:

391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.0916

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.0413

Gnomad FIN

AF:

0.0546

Gnomad MID

AF:

0.0732

Gnomad NFE

AF:

0.0686

Gnomad OTH

AF:

0.0738

GnomAD2 exomes

AF:

0.0746

AC:

18742

AN:

251084

AF XY:

0.0718

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.0878

Gnomad EAS exome

AF:

0.0985

Gnomad FIN exome

AF:

0.0553

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.0690

GnomAD4 exome

AF:

0.0688

AC:

100604

AN:

1461536

Hom.:

3898

Cov.:

AF XY:

0.0678

AC XY:

49327

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.0158

AC:

529

AN:

33472

American (AMR)

AF:

0.137

AC:

6120

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0882

AC:

2303

AN:

26118

East Asian (EAS)

AF:

0.120

AC:

4763

AN:

39666

South Asian (SAS)

AF:

0.0392

AC:

3380

AN:

86246

European-Finnish (FIN)

AF:

0.0564

AC:

3014

AN:

53404

Middle Eastern (MID)

AF:

0.0439

AC:

253

AN:

5764

European-Non Finnish (NFE)

AF:

0.0684

AC:

76073

AN:

1111800

Other (OTH)

AF:

0.0691

AC:

4169

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4581

9162

13742

18323

22904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2870

5740

8610

11480

14350

<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:

0.0602

AC:

9158

AN:

152110

Hom.:

391

Cov.:

AF XY:

0.0612

AC XY:

4552

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0180

AC:

749

AN:

41520

American (AMR)

AF:

0.128

AC:

1952

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0916

AC:

318

AN:

3470

East Asian (EAS)

AF:

0.0995

AC:

515

AN:

5176

South Asian (SAS)

AF:

0.0411

AC:

198

AN:

4820

European-Finnish (FIN)

AF:

0.0546

AC:

578

AN:

10578

Middle Eastern (MID)

AF:

0.0719

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0686

AC:

4663

AN:

67974

Other (OTH)

AF:

0.0720

AC:

152

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

432

865

1297

1730

2162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0658

Hom.:

832

Bravo

AF:

0.0645

Asia WGS

AF:

0.0600

AC:

209

AN:

3478

EpiCase

AF:

0.0701

EpiControl

AF:

0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 14, 2017

Athena Diagnostics

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

- -

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant Parkinson disease 8

Benign:3Other:1

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. -

Jan 31, 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

- -

Sep 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.1

(source)

DANN

Benign

0.56

PhyloP100

1.2

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