chr12-40235634-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_198578.4(LRRK2):ā€‹c.356T>Cā€‹(p.Leu119Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00182 in 1,602,432 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L119F) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0014 ( 0 hom., cov: 32)
Exomes š‘“: 0.0019 ( 4 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

4
7
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 5.35
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.026334167).
BP6
Variant 12-40235634-T-C is Benign according to our data. Variant chr12-40235634-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39167.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=3, Uncertain_significance=1}. Variant chr12-40235634-T-C is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRK2NM_198578.4 linkuse as main transcriptc.356T>C p.Leu119Pro missense_variant 4/51 ENST00000298910.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRK2ENST00000298910.12 linkuse as main transcriptc.356T>C p.Leu119Pro missense_variant 4/511 NM_198578.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00137
AC:
209
AN:
152242
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00150
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00229
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00125
AC:
313
AN:
251148
Hom.:
0
AF XY:
0.00136
AC XY:
185
AN XY:
135772
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.00119
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000926
Gnomad NFE exome
AF:
0.00225
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00187
AC:
2713
AN:
1450072
Hom.:
4
Cov.:
29
AF XY:
0.00184
AC XY:
1329
AN XY:
722338
show subpopulations
Gnomad4 AFR exome
AF:
0.000301
Gnomad4 AMR exome
AF:
0.00152
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.000113
Gnomad4 NFE exome
AF:
0.00228
Gnomad4 OTH exome
AF:
0.00175
GnomAD4 genome
AF:
0.00137
AC:
209
AN:
152360
Hom.:
0
Cov.:
32
AF XY:
0.00128
AC XY:
95
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000601
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00229
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00224
Hom.:
0
Bravo
AF:
0.00135
TwinsUK
AF:
0.00216
AC:
8
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00174
AC:
15
ExAC
AF:
0.00128
AC:
156
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00300
EpiControl
AF:
0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:2Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024LRRK2: BS1 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 19, 2022Reported previously in individuals with Parkinson disease, however L119P was also seen in control subjects (Jasinska-Myga et al., 2010; Ross et al., 2011; Benitez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28130640, 25466404, 31980526, 33836114, 31996268, 29369408, 27393345, 32557143, 28842327, 20721913, 25174650, 27294386, 21885347, 27094865, 34542912, Kalogeropulou2022[functionalstudy], 33454605) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
.;T;T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.67
T;T;T
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.026
T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
1.9
.;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Uncertain
0.46
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.0050
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.92, 0.93
MVP
0.88
MPC
0.55
ClinPred
0.040
T
GERP RS
5.8
Varity_R
0.84
gMVP
0.79

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: rs33995463; hg19: chr12-40629436; API