rs60185966

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_198578.4(LRRK2):c.3683G>C(p.Ser1228Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,613,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30613083).

BP6

Variant 12-40304040-G-C is Benign according to our data. Variant chr12-40304040-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39171.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.3683G>C	p.Ser1228Thr	missense_variant	27/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.3683G>C	p.Ser1228Thr	missense_variant	27/51	1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251042

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000310

AC:

453

AN:

1461530

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

210

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000401

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000171

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000338

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2023	ClinVar contains an entry for this variant (Variation ID: 39171). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LRRK2 function (PMID: 20642453, 35950872). 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. This missense change has been observed in individual(s) with Parkinson disease (PMID: 16251215, 18213618, 21885347). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs60185966, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1228 of the LRRK2 protein (p.Ser1228Thr). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

LRRK2: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.047

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.9

.;M

MutationTaster

Benign

0.91

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.060

T;T

Polyphen

0.55

P;P

Vest4

0.70

MVP

0.80

MPC

0.093

ClinPred

0.14

GERP RS

-0.14

Varity_R

0.11

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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