12-40237989-T-C

Variant names:

• chr12-40237989-T-C
• rs10878245
• NM_198578.4:c.457T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.457T>C​(p.Leu153Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,609,940 control chromosomes in the GnomAD database, including 279,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20577 hom., cov: 32)
  • Exomes 𝑓: 0.59 (258528 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.562
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-40237989-T-C is Benign according to our data. Variant chr12-40237989-T-C is described in ClinVar as Benign. ClinVar VariationId is 39192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.562 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.457T>C	p.Leu153Leu	synonymous	Exon 5 of 51	NP_940980.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.457T>C	p.Leu153Leu	synonymous	Exon 5 of 51	ENSP00000298910.7
	LRRK2	ENST00000680790.1		c.457T>C	p.Leu153Leu	synonymous	Exon 5 of 49	ENSP00000505335.1
	LRRK2	ENST00000343742.6	TSL:5	c.457T>C	p.Leu153Leu	synonymous	Exon 5 of 27	ENSP00000341930.2

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77337 AN: 151896 Hom.: 20563 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.512

GnomAD2 exomes AF: 0.521 AC: 130500 AN: 250672 AF XY: 0.535

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.590 AC: 859695 AN: 1457926 Hom.: 258528 Cov.: 37 AF XY: 0.591 AC XY: 428840 AN XY: 725502

African (AFR) AF: 0.380 AC: 12682 AN: 33402

American (AMR) AF: 0.339 AC: 15137 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 13913 AN: 26090

East Asian (EAS) AF: 0.351 AC: 13884 AN: 39602

South Asian (SAS) AF: 0.610 AC: 52558 AN: 86152

European-Finnish (FIN) AF: 0.524 AC: 27715 AN: 52908

Middle Eastern (MID) AF: 0.453 AC: 2605 AN: 5752

European-Non Finnish (NFE) AF: 0.620 AC: 687384 AN: 1109052

Other (OTH) AF: 0.561 AC: 33817 AN: 60274

GnomAD4 genome AF: 0.509 AC: 77385 AN: 152014 Hom.: 20577 Cov.: 32 AF XY: 0.502 AC XY: 37294 AN XY: 74322

African (AFR) AF: 0.389 AC: 16130 AN: 41478

American (AMR) AF: 0.405 AC: 6184 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1831 AN: 3466

East Asian (EAS) AF: 0.357 AC: 1844 AN: 5166

South Asian (SAS) AF: 0.609 AC: 2937 AN: 4824

European-Finnish (FIN) AF: 0.511 AC: 5384 AN: 10540

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41403 AN: 67954

Other (OTH) AF: 0.512 AC: 1081 AN: 2112

Alfa AF: 0.544 Hom.: 19074

Bravo AF: 0.491

Asia WGS AF: 0.463 AC: 1608 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autosomal dominant Parkinson disease 8 Benign:2 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10878245; hg19: chr12-40631791; COSMIC: COSV54154315;