rs60545352

Positions:

chr12-40364884-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The ENST00000298910.12(LRRK2):c.7224G>A(p.Met2408Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2408K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

LRRK2
ENST00000298910.12 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1O:1

Conservation

PhyloP100: 1.40

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 links:

LOC105369736 (HGNC:):

LOC105369736 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a mutagenesis_site No effect on WD domain homodimerization. No effect on kinase activity. (size 0) in uniprot entity LRRK2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.10231966).

BS2

High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.7224G>A	p.Met2408Ile	missense_variant	49/51	ENST00000298910.12	NP_940980.4
LOC105369736	XR_944868.3 linkuse as main transcript	n.485-10057C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.7224G>A	p.Met2408Ile	missense_variant	49/51	1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250234

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1460252

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000334

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The LRRK2 p.Met2408Ile variant was not identified in Clinvitae, Cosmic, MutDB and LOVD 3.0. The variant was identified in dbSNP (ID: rs60545352) and in ClinVar (classified as a VUS for Parkinson disease 8, autosomal dominant by GeneReviews). The variant was also identified in control databases in 6 of 281598 chromosomes at a frequency of 0.000021 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7162 chromosomes (freq: 0.00014), Latino in 3 of 35242 chromosomes (freq: 0.000085), European (non-Finnish) in 2 of 128360 chromosomes (freq: 0.000016), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. In a study analyzing LRRK2 variants in patients with familial Parkinson's disease, the p.Met2408Ile variant was identified in one proband with familial PD, but was also found in an unaffected individual from another family and in two healthy control subjects, suggesting this variant does not segregate with disease (Jasinska-Myga_2010_PMID: 20721913). The variant is located in the WD40 protein domain (O.A. Ross_2011_PMID: 21885347), however the p.Met2408 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Autosomal dominant Parkinson disease 8

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.75

M_CAP

Benign

0.011

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.42

REVEL

Benign

0.053

Sift

Benign

0.50

Sift4G

Benign

0.34

Polyphen

0.014

Vest4

0.17

MutPred

0.24

Loss of sheet (P = 0.0054);

MVP

0.79

MPC

0.22

ClinPred

0.042

GERP RS

3.5

Varity_R

0.26

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over