12-40363526-G-A

Position:

chr12-40363526-G-A

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 Likely benign.

Frequency

Genomes: 𝑓 0.00084 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 22 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

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]

LRRK2 links:

LOC105369736 (HGNC:):

LOC105369736 links:

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/exons	MANE	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.7153G>A	p.Gly2385Arg	missense_variant	48/51	ENST00000298910.12
LOC105369736	XR_944868.3 linkuse as main transcript	n.485-8699C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.7153G>A	p.Gly2385Arg	missense_variant	48/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000823

AC:

125

AN:

151846

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.00102

AC XY:

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.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.00404

AC:

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

risk factor, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, flagged submission	provider interpretation	Codex Genetics Limited	Feb 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 09, 2020

- -

Parkinson disease

Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2020

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

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0068

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.25

REVEL

Benign

0.044

Sift

Benign

0.19

Sift4G

Uncertain

0.032

Polyphen

0.074

Vest4

0.37

MutPred

0.42

Gain of MoRF binding (P = 0.0773);

MVP

0.70

MPC

0.24

ClinPred

0.045

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.

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