dbSNP rs281865052: LRRK2:p.Met1869Val (chr12-40323255-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_198578.4(LRRK2):c.5605A>G(p.Met1869Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1869T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 5.96

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

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.5605A>G	p.Met1869Val	missense	Exon 38 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.5605A>G	p.Met1869Val	missense	Exon 38 of 51	ENSP00000298910.7	Q5S007
LRRK2	ENST00000430804.5	TSL:1	n.*2278A>G		non_coding_transcript_exon	Exon 17 of 30	ENSP00000410821.1	H7C3B6
LRRK2	ENST00000430804.5	TSL:1	n.*2278A>G		3_prime_UTR	Exon 17 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant Parkinson disease 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

0.067

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.69

PhyloP100

6.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.41

Sift

Benign

0.082

Sift4G

Uncertain

0.013

Polyphen

0.14

Vest4

0.84

MutPred

0.77

Loss of stability (P = 0.0308)

MVP

0.82

MPC

0.095

ClinPred

0.84

GERP RS

6.2

Varity_R

0.67

gMVP

0.44

Mutation Taster

=61/39

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over