rs34778348

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_198578.4(LRRK2):​c.7153G>A​(p.Gly2385Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000787 in 1,611,766 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. G2385G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00084 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00078 ( 22 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

4
14

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:1U:2B:2O:3

Conservation

PhyloP100: 5.68
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=0.0067643523).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000836 (127/151964) while in subpopulation EAS AF= 0.0238 (123/5162). AF 95% confidence interval is 0.0204. There are 5 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRRK2NM_198578.4 linkc.7153G>A p.Gly2385Arg missense_variant Exon 48 of 51 ENST00000298910.12 NP_940980.4 Q5S007Q17RV3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRRK2ENST00000298910.12 linkc.7153G>A p.Gly2385Arg missense_variant Exon 48 of 51 1 NM_198578.4 ENSP00000298910.7 Q5S007

Frequencies

GnomAD3 genomes
AF:
0.000823
AC:
125
AN:
151846
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0234
Gnomad SAS
AF:
0.000623
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00171
AC:
429
AN:
250734
Hom.:
7
AF XY:
0.00170
AC XY:
231
AN XY:
135518
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0218
Gnomad SAS exome
AF:
0.000556
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.000821
GnomAD4 exome
AF:
0.000782
AC:
1142
AN:
1459802
Hom.:
22
Cov.:
33
AF XY:
0.000819
AC XY:
595
AN XY:
726230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0266
Gnomad4 SAS exome
AF:
0.000534
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000481
GnomAD4 genome
AF:
0.000836
AC:
127
AN:
151964
Hom.:
5
Cov.:
32
AF XY:
0.00102
AC XY:
76
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0238
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.00136
Hom.:
7
Bravo
AF:
0.00105
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00158
AC:
192
Asia WGS
AF:
0.00404
AC:
14
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor
Submissions summary: Pathogenic:1Uncertain:2Benign:2Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:1Uncertain:1Benign:2Other:2
Oct 01, 2008
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 28, 2019
Codex Genetics Limited
Significance: Pathogenic
Review Status: flagged submission
Collection Method: provider interpretation

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Apr 09, 2020
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Parkinson disease Other:1
Sep 21, 2020
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: risk factor
Review Status: criteria provided, single submitter
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.47
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.14
T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.28
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.52
T
MetaRNN
Benign
0.0068
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.25
N
REVEL
Benign
0.044
Sift
Benign
0.19
T
Sift4G
Uncertain
0.032
D
Polyphen
0.074
B
Vest4
0.37
MutPred
0.42
Gain of MoRF binding (P = 0.0773);
MVP
0.70
MPC
0.24
ClinPred
0.045
T
GERP RS
4.4
Varity_R
0.34
gMVP
0.36

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: rs34778348; hg19: chr12-40757328; COSMIC: COSV54154420; API