rs33995883

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.6241A>G(p.Asn2081Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0168 in 1,612,916 control chromosomes in the GnomAD database, including 379 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2081I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.017 ( 356 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 7.19

Publications

88 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: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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 (MetaRNN=0.00891602).

BP6

Variant 12-40346884-A-G is Benign according to our data. Variant chr12-40346884-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.6241A>G	p.Asn2081Asp	missense	Exon 42 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.6241A>G	p.Asn2081Asp	missense	Exon 42 of 51	ENSP00000298910.7	Q5S007
LRRK2	ENST00000430804.5	TSL:1	n.*2914A>G		non_coding_transcript_exon	Exon 21 of 30	ENSP00000410821.1	H7C3B6
LRRK2	ENST00000430804.5	TSL:1	n.*2914A>G		3_prime_UTR	Exon 21 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2067

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0524

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0325

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0176

AC:

4406

AN:

250168

AF XY:

0.0190

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00956

Gnomad ASJ exome

AF:

0.0608

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.00315

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0171

AC:

25013

AN:

1460604

Hom.:

356

Cov.:

AF XY:

0.0178

AC XY:

12935

AN XY:

726576

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33414

American (AMR)

AF:

0.0101

AC:

452

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.0552

AC:

1440

AN:

26094

East Asian (EAS)

AF:

0.000328

AC:

AN:

39622

South Asian (SAS)

AF:

0.0338

AC:

2905

AN:

85930

European-Finnish (FIN)

AF:

0.00414

AC:

221

AN:

53406

Middle Eastern (MID)

AF:

0.0794

AC:

453

AN:

5708

European-Non Finnish (NFE)

AF:

0.0163

AC:

18121

AN:

1111530

Other (OTH)

AF:

0.0218

AC:

1315

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1068

2136

3205

4273

5341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.0136

AC:

2066

AN:

152312

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1014

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00332

AC:

138

AN:

41562

American (AMR)

AF:

0.0137

AC:

210

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

182

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.0329

AC:

159

AN:

4832

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0183

AC:

1243

AN:

68020

Other (OTH)

AF:

0.0246

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0186

Hom.:

100

Bravo

AF:

0.0130

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0191

AC:

164

ExAC

AF:

0.0175

AC:

2118

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0263

EpiControl

AF:

0.0237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant Parkinson disease 8 (4)

not provided (3)

not specified (3)

Parkinson disease;C0242422:Parkinsonian disorder;C0393568:Vascular parkinsonism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.13

PhyloP100

7.2

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.081

Sift4G

Uncertain

0.035

Polyphen

0.39

Vest4

0.19

MPC

1.9

ClinPred

0.015

GERP RS

5.6

PromoterAI

0.025

Neutral

(source)

Varity_R

0.46

gMVP

0.43

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over