rs7966550

Variant names:

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.2857T>C(p.Leu953Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,543,352 control chromosomes in the GnomAD database, including 9,795 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. L953L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.092 ( 796 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8999 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.974

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-40294893-T-C is Benign according to our data. Variant chr12-40294893-T-C is described in ClinVar as Benign. ClinVar VariationId is 39156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.974 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.2857T>C	p.Leu953Leu	synonymous_variant	Exon 22 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.2857T>C	p.Leu953Leu	synonymous_variant	Exon 22 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes

AF:

0.0916

AC:

13926

AN:

151954

Hom.:

796

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0255

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.0619

Gnomad FIN

AF:

0.0820

Gnomad MID

AF:

0.137

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.104

AC:

26057

AN:

249754

AF XY:

0.105

show subpopulations

Gnomad AFR exome

AF:

0.0213

Gnomad AMR exome

AF:

0.0832

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.181

Gnomad FIN exome

AF:

0.0820

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.120

GnomAD4 exome

AF:

0.109

AC:

151772

AN:

1391280

Hom.:

8999

Cov.:

AF XY:

0.108

AC XY:

75102

AN XY:

694816

show subpopulations

African (AFR)

AF:

0.0206

AC:

667

AN:

32376

American (AMR)

AF:

0.0866

AC:

3837

AN:

44326

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

2853

AN:

25458

East Asian (EAS)

AF:

0.156

AC:

6074

AN:

38934

South Asian (SAS)

AF:

0.0610

AC:

5042

AN:

82600

European-Finnish (FIN)

AF:

0.0828

AC:

4343

AN:

52468

Middle Eastern (MID)

AF:

0.126

AC:

632

AN:

5022

European-Non Finnish (NFE)

AF:

0.116

AC:

122268

AN:

1052314

Other (OTH)

AF:

0.105

AC:

6056

AN:

57782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

5166

10332

15499

20665

25831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4274

8548

12822

17096

21370

<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:

0.0916

AC:

13932

AN:

152072

Hom.:

796

Cov.:

AF XY:

0.0897

AC XY:

6669

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0255

AC:

1060

AN:

41554

American (AMR)

AF:

0.112

AC:

1710

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

383

AN:

3466

East Asian (EAS)

AF:

0.156

AC:

811

AN:

5184

South Asian (SAS)

AF:

0.0621

AC:

299

AN:

4814

European-Finnish (FIN)

AF:

0.0820

AC:

867

AN:

10572

Middle Eastern (MID)

AF:

0.134

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.124

AC:

8399

AN:

67918

Other (OTH)

AF:

0.110

AC:

232

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

642

1284

1927

2569

3211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.111

Hom.:

2162

Bravo

AF:

0.0940

Asia WGS

AF:

0.102

AC:

355

AN:

3460

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

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. -

Sep 29, 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

- -

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 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

- -

not specified

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

(source)

DANN

Benign

0.60

PhyloP100

-0.97

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