rs200437744

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_198578.4(LRRK2):ā€‹c.856C>Gā€‹(p.Leu286Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,450 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00020 ( 0 hom., cov: 32)
Exomes š‘“: 0.00025 ( 1 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

1
7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13076845).
BP6
Variant 12-40249843-C-G is Benign according to our data. Variant chr12-40249843-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236286.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRK2NM_198578.4 linkc.856C>G p.Leu286Val missense_variant 8/51 ENST00000298910.12 NP_940980.4 Q5S007Q17RV3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRK2ENST00000298910.12 linkc.856C>G p.Leu286Val missense_variant 8/511 NM_198578.4 ENSP00000298910.7 Q5S007

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152014
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
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:
0.000353
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000147
AC:
37
AN:
250988
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135642
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000521
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:
0.000150
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000246
AC:
360
AN:
1461436
Hom.:
1
Cov.:
31
AF XY:
0.000226
AC XY:
164
AN XY:
727016
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000492
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:
0.000298
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152014
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74242
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000328
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000353
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000559
Hom.:
0
Bravo
AF:
0.000227
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000327
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 22, 2023This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 286 of the LRRK2 protein (p.Leu286Val). This variant is present in population databases (rs200437744, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Parkinson disease (PMID: 24082139, 26213354). ClinVar contains an entry for this variant (Variation ID: 236286). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRRK2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria providedliterature onlyGeneReviewsDec 11, 2014- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 12, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.090
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.055
.;T;T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.86
D;D;D
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.36
T
MutationAssessor
Uncertain
2.1
.;.;M
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.5
N;N;N
REVEL
Benign
0.17
Sift
Benign
0.17
T;D;T
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.59, 0.76
MutPred
0.32
.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP
0.83
MPC
0.47
ClinPred
0.27
T
GERP RS
4.7
Varity_R
0.13
gMVP
0.49

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.

Other links and lift over

dbSNP: rs200437744; hg19: chr12-40643645; API