12-40237989-T-C

Position:

• chr12-40237989-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.457T>C​(p.Leu153=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 39192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40237989-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.457T>C	p.Leu153=	synonymous_variant	5/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.457T>C	p.Leu153=	synonymous_variant	5/51	1	NM_198578.4	P1

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

GnomAD3 exomes AF: 0.521 AC: 130500 AN: 250672 Hom.: 35779 AF XY: 0.535 AC XY: 72580 AN XY: 135546

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 SAS exome AF: 0.609

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

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.533

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.620

Gnomad4 OTH exome AF: 0.561

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

Gnomad4 AFR AF: 0.389

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.528

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.609

Gnomad4 FIN AF: 0.511

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.512

Alfa AF: 0.552 Hom.: 14088

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

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Autosomal dominant Parkinson disease 8 Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	GeneDx	Aug 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.1
DANN	Benign	0.80

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