rs41286460

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198578.4(LRRK2):c.5510-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,610,342 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 19 hom. )

Consequence

LRRK2
NM_198578.4 intron

Scores

Splicing: ADA: 0.00002014

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.11

Publications

3 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=-0.87).

BP6

Variant 12-40323151-A-G is Benign according to our data. Variant chr12-40323151-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00322 (4693/1458164) while in subpopulation MID AF = 0.0179 (103/5756). AF 95% confidence interval is 0.0151. There are 19 homozygotes in GnomAdExome4. There are 2377 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 401 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.5510-9A>G		intron_variant	Intron 37 of 50	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.5510-9A>G		intron_variant	Intron 37 of 50	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.00263

AC:

400

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00396

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00281

AC:

704

AN:

250682

AF XY:

0.00306

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00716

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00322

AC:

4693

AN:

1458164

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

2377

AN XY:

725500

show subpopulations

African (AFR)

AF:

0.000809

AC:

AN:

33394

American (AMR)

AF:

0.00222

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00832

AC:

217

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00294

AC:

253

AN:

85956

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5756

European-Non Finnish (NFE)

AF:

0.00340

AC:

3770

AN:

1109148

Other (OTH)

AF:

0.00317

AC:

191

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

220

440

660

880

1100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00264

AC:

401

AN:

152178

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41560

American (AMR)

AF:

0.00229

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00396

AC:

269

AN:

67934

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00385

Hom.:

Bravo

AF:

0.00243

Asia WGS

AF:

0.00116

AC:

AN:

3474

EpiCase

AF:

0.00360

EpiControl

AF:

0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3

Jan 12, 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 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Dec 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Dec 02, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parkinson Disease, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LRRK2-related disorder

Benign:1

Dec 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.067

(source)

DANN

Benign

0.41

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.010

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