rs33995883

Variant names:

• chr12-40346884-A-G
• rs33995883
• NM_198578.4:c.6241A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-40346884-A-G
• chr12-40346884-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 7.19
• Publications: 88 publications found

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

ENSG00000258167 (HGNC:):

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.6241A>G	p.Asn2081Asp	missense_variant	Exon 42 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.6241A>G	p.Asn2081Asp	missense_variant	Exon 42 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2067 AN: 152194 Hom.: 24 Cov.: 32

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

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.: 31 AF XY: 0.0178 AC XY: 12935 AN XY: 726576

African (AFR) AF: 0.00278 AC: 93 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: 13 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

GnomAD4 genome AF: 0.0136 AC: 2066 AN: 152312 Hom.: 23 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74486

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: 1 AN: 5194

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1243 AN: 68020

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0186 Hom.: 100

Bravo AF: 0.0130

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0191 AC: 164

ExAC AF: 0.0175 AC: 2118

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0263

EpiControl AF: 0.0237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other: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. -

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32677286, 29795570, 29321258, 25378673) -

Sep 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Parkinson disease;C0242422:Parkinsonian disorder;C0393568:Vascular parkinsonism Benign:1

Oct 01, 2024

The Egyptian Network for Neurodegenerative Diseases (ENND), The American University in Cairo

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

This variant (MAF 0.00978435 in 1000Genomes /0.0108 in gnomAD) is currently classified as likely benign variant based on ACMG criteria. same variant was previously linked to increased PD risk with functionally validated increased LRRK2 activation and enhanced Rab10 phosphorylation. The mutation disrupts the hydrophilic interactions between kinase and LRR domains causing an increase in LRRK2 activity (PMID:35950872). Variant falls within the kinase domain and is an eQTL for LRRK2 expression in brain tissue according to GTEx. The CADD score is 23.5, supporting potential deleteriousness. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.13	N
PhyloP100		7.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.081	T
Sift4G	Uncertain	0.035	D
Polyphen		0.39	B
Vest4		0.19
MPC		1.9
ClinPred		0.015	T
GERP RS		5.6
PromoterAI		0.025	Neutral
Varity_R		0.46
gMVP		0.43
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs33995883; hg19: chr12-40740686; COSMIC: COSV104599035;