NM_198578.4:c.1653C>G

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.1653C>G(p.Asn551Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,596,920 control chromosomes in the GnomAD database, including 5,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N551N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.098 ( 892 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4312 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.392

Publications

117 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=0.0017452538).

BP6

Variant 12-40263898-C-G is Benign according to our data. Variant chr12-40263898-C-G is described in ClinVar as Benign. ClinVar VariationId is 39139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.1653C>G	p.Asn551Lys	missense_variant	Exon 14 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.1653C>G	p.Asn551Lys	missense_variant	Exon 14 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes

AF:

0.0976

AC:

14840

AN:

152000

Hom.:

888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.0555

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0685

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0868

AC:

21777

AN:

250972

AF XY:

0.0806

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.0948

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.0559

Gnomad NFE exome

AF:

0.0720

Gnomad OTH exome

AF:

0.0758

GnomAD4 exome

AF:

0.0717

AC:

103567

AN:

1444802

Hom.:

4312

Cov.:

AF XY:

0.0701

AC XY:

50487

AN XY:

719822

show subpopulations

African (AFR)

AF:

0.136

AC:

4502

AN:

33038

American (AMR)

AF:

0.163

AC:

7283

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.0951

AC:

2472

AN:

25990

East Asian (EAS)

AF:

0.125

AC:

4921

AN:

39490

South Asian (SAS)

AF:

0.0388

AC:

3329

AN:

85730

European-Finnish (FIN)

AF:

0.0576

AC:

3071

AN:

53292

Middle Eastern (MID)

AF:

0.0510

AC:

291

AN:

5706

European-Non Finnish (NFE)

AF:

0.0666

AC:

73083

AN:

1097180

Other (OTH)

AF:

0.0772

AC:

4615

AN:

59748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

4296

8592

12889

17185

21481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2814

5628

8442

11256

14070

<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:

0.0977

AC:

14861

AN:

152118

Hom.:

892

Cov.:

AF XY:

0.0984

AC XY:

7319

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.141

AC:

5849

AN:

41504

American (AMR)

AF:

0.160

AC:

2441

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

356

AN:

3470

East Asian (EAS)

AF:

0.100

AC:

518

AN:

5178

South Asian (SAS)

AF:

0.0422

AC:

203

AN:

4816

European-Finnish (FIN)

AF:

0.0555

AC:

587

AN:

10578

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0685

AC:

4658

AN:

67990

Other (OTH)

AF:

0.102

AC:

215

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

662

1323

1985

2646

3308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0747

Hom.:

352

Bravo

AF:

0.109

TwinsUK

AF:

0.0639

AC:

237

ALSPAC

AF:

0.0638

AC:

246

ESP6500AA

AF:

0.138

AC:

609

ESP6500EA

AF:

0.0722

AC:

621

ExAC

AF:

0.0858

AC:

10422

Asia WGS

AF:

0.0740

AC:

257

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31487119, 31182772, 30917570, 29321258, 20186690, 23913756, 20721913)

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 29, 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

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Mar 06, 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.

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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;.;M

PhyloP100

0.39

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

N;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0070

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.0

ClinPred

0.038

GERP RS

2.7

Varity_R

0.43

gMVP

0.63

Mutation Taster

=64/36

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