rs1427263

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.4872C>A(p.Gly1624Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,608,450 control chromosomes in the GnomAD database, including 361,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37378 hom., cov: 32)

Exomes 𝑓: 0.66 ( 323642 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.535

Publications

47 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=-0.38).

BP6

Variant 12-40320032-C-A is Benign according to our data. Variant chr12-40320032-C-A is described in ClinVar as Benign. ClinVar VariationId is 39197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.535 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4872C>A	p.Gly1624Gly	synonymous_variant	Exon 34 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.4872C>A	p.Gly1624Gly	synonymous_variant	Exon 34 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106016

AN:

151782

Hom.:

37343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.770

Gnomad AMI

AF:

0.664

Gnomad AMR

AF:

0.713

Gnomad ASJ

AF:

0.612

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.719

Gnomad FIN

AF:

0.782

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.673

GnomAD2 exomes

AF:

0.679

AC:

169662

AN:

249798

AF XY:

0.676

show subpopulations

Gnomad AFR exome

AF:

0.766

Gnomad AMR exome

AF:

0.731

Gnomad ASJ exome

AF:

0.610

Gnomad EAS exome

AF:

0.502

Gnomad FIN exome

AF:

0.777

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.673

GnomAD4 exome

AF:

0.664

AC:

967676

AN:

1456552

Hom.:

323642

Cov.:

AF XY:

0.665

AC XY:

482154

AN XY:

724650

show subpopulations

African (AFR)

AF:

0.773

AC:

25738

AN:

33286

American (AMR)

AF:

0.727

AC:

32391

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

15922

AN:

26024

East Asian (EAS)

AF:

0.508

AC:

20120

AN:

39574

South Asian (SAS)

AF:

0.719

AC:

61660

AN:

85760

European-Finnish (FIN)

AF:

0.772

AC:

41214

AN:

53360

Middle Eastern (MID)

AF:

0.605

AC:

3469

AN:

5734

European-Non Finnish (NFE)

AF:

0.656

AC:

726807

AN:

1108084

Other (OTH)

AF:

0.670

AC:

40355

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

16509

33018

49528

66037

82546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18996

37992

56988

75984

94980

<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:

0.699

AC:

106109

AN:

151898

Hom.:

37378

Cov.:

AF XY:

0.705

AC XY:

52334

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.770

AC:

31909

AN:

41450

American (AMR)

AF:

0.713

AC:

10866

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

2122

AN:

3466

East Asian (EAS)

AF:

0.508

AC:

2619

AN:

5156

South Asian (SAS)

AF:

0.720

AC:

3471

AN:

4824

European-Finnish (FIN)

AF:

0.782

AC:

8261

AN:

10562

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.658

AC:

44665

AN:

67894

Other (OTH)

AF:

0.669

AC:

1410

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1650

3301

4951

6602

8252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.670

Hom.:

50932

Bravo

AF:

0.691

Asia WGS

AF:

0.633

AC:

2196

AN:

3474

EpiCase

AF:

0.649

EpiControl

AF:

0.644

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

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 05, 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

BayesDel_noAF

Benign

-0.38

CADD

Benign

5.6

(source)

DANN

Benign

0.65

PhyloP100

0.54

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