12-40263898-C-G

Position:

chr12-40263898-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198578.4(LRRK2):c.1653C>G(p.Asn551Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,596,920 control chromosomes in the GnomAD database, including 5,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N551N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.098 ( 892 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4312 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.392

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017452538).

BP6

Variant 12-40263898-C-G is Benign according to our data. Variant chr12-40263898-C-G is described in ClinVar as [Benign]. Clinvar id is 39139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40263898-C-G is described in Lovd as [Benign]. Variant chr12-40263898-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.1653C>G	p.Asn551Lys	missense_variant	14/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.1653C>G	p.Asn551Lys	missense_variant	14/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0976

AC:

14840

AN:

152000

Hom.:

888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.0555

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0685

Gnomad OTH

AF:

0.104

GnomAD3 exomes

AF:

0.0868

AC:

21777

AN:

250972

Hom.:

1184

AF XY:

0.0806

AC XY:

10935

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.0948

Gnomad EAS exome

AF:

0.104

Gnomad SAS exome

AF:

0.0395

Gnomad FIN exome

AF:

0.0559

Gnomad NFE exome

AF:

0.0720

Gnomad OTH exome

AF:

0.0758

GnomAD4 exome

AF:

0.0717

AC:

103567

AN:

1444802

Hom.:

4312

Cov.:

AF XY:

0.0701

AC XY:

50487

AN XY:

719822

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.0951

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.0388

Gnomad4 FIN exome

AF:

0.0576

Gnomad4 NFE exome

AF:

0.0666

Gnomad4 OTH exome

AF:

0.0772

GnomAD4 genome

AF:

0.0977

AC:

14861

AN:

152118

Hom.:

892

Cov.:

AF XY:

0.0984

AC XY:

7319

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.160

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.100

Gnomad4 SAS

AF:

0.0422

Gnomad4 FIN

AF:

0.0555

Gnomad4 NFE

AF:

0.0685

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0747

Hom.:

352

Bravo

AF:

0.109

TwinsUK

AF:

0.0639

AC:

237

ALSPAC

AF:

0.0638

AC:

246

ESP6500AA

AF:

0.138

AC:

609

ESP6500EA

AF:

0.0722

AC:

621

ExAC

AF:

0.0858

AC:

10422

Asia WGS

AF:

0.0740

AC:

257

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	This variant is associated with the following publications: (PMID: 31487119, 31182772, 30917570, 29321258, 20186690, 23913756, 20721913) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2017	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.032

P;P

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

N;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0070

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.88, 1.0

.;P;D

Vest4

0.33, 0.78

MutPred

0.57

.;Gain of MoRF binding (P = 0.034);Gain of MoRF binding (P = 0.034);

MPC

0.49

ClinPred

0.038

GERP RS

2.7

Varity_R

0.43

gMVP

0.63

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