rs3761863

chr12-40364850-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):c.7190T>C(p.Met2397Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,607,482 control chromosomes in the GnomAD database, including 342,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29240 hom., cov: 31)
  • Exomes 𝑓: 0.65 (312933 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.378

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]

LOC105369736 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.09017E-6).
• BP6: Variant 12-40364850-T-C is Benign according to our data. Variant chr12-40364850-T-C is described in ClinVar as [Benign]. Clinvar id is 308647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40364850-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.7190T>C	p.Met2397Thr	missense_variant	49/51	ENST00000298910.12
LOC105369736	XR_944868.3	n.485-10023A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.7190T>C	p.Met2397Thr	missense_variant	49/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93446 AN: 151576 Hom.: 29223 Cov.: 31

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.609

GnomAD3 exomes AF: 0.617 AC: 153306 AN: 248412 Hom.: 48382 AF XY: 0.623 AC XY: 83757 AN XY: 134394

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.468

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.665

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.653 AC: 950317 AN: 1455788 Hom.: 312933 Cov.: 34 AF XY: 0.653 AC XY: 473248 AN XY: 724536

Gnomad4 AFR exome AF: 0.522

Gnomad4 AMR exome AF: 0.508

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.462

Gnomad4 SAS exome AF: 0.630

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.669

Gnomad4 OTH exome AF: 0.642

GnomAD4 genome AF: 0.616 AC: 93512 AN: 151694 Hom.: 29240 Cov.: 31 AF XY: 0.619 AC XY: 45906 AN XY: 74138

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.749

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.605

Alfa AF: 0.646 Hom.: 75724

Bravo AF: 0.598

TwinsUK AF: 0.650 AC: 2410

ALSPAC AF: 0.665 AC: 2561

ESP6500AA AF: 0.529 AC: 2328

ESP6500EA AF: 0.655 AC: 5634

ExAC AF: 0.617 AC: 74804

Asia WGS AF: 0.529 AC: 1839 AN: 3478

EpiCase AF: 0.653

EpiControl AF: 0.652

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal dominant Parkinson disease 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 26844546, 25521227, 30917570, 25378673) -

Leprosy, susceptibility to, 1 Other:1

confers sensitivity, no assertion criteria provided

case-control

Centro Dermatológico Federico Lleras Acosta, Hospital Universitario Centro Dermatológico Federico Lleras Acosta

Jun 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.22
Dann	Benign	0.13
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000031	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.098
Sift	Benign	0.47	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.23
ClinPred		0.00052	T
GERP RS		3.0
Varity_R		0.12
gMVP		0.54

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

Other links and lift over

dbSNP: rs3761863; hg19: chr12-40758652; COSMIC: COSV54153532;