rs11176013

Positions:

• chr12-40320071-A-G

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.4911A>G​(p.Lys1637=) variant causes a synonymous change. The variant allele was found at a frequency of 0.558 in 1,608,610 control chromosomes in the GnomAD database, including 252,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24558 hom., cov: 32)
  • Exomes 𝑓: 0.56 (227839 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 4.58

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-40320071-A-G is Benign according to our data. Variant chr12-40320071-A-G is described in ClinVar as [Benign]. Clinvar id is 39199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40320071-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.4911A>G	p.Lys1637=	synonymous_variant	34/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.4911A>G	p.Lys1637=	synonymous_variant	34/51	1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86053 AN: 151726 Hom.: 24541 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.557

GnomAD3 exomes AF: 0.576 AC: 143530 AN: 249074 Hom.: 41995 AF XY: 0.576 AC XY: 77636 AN XY: 134764

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.476

Gnomad SAS exome AF: 0.691

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.557 AC: 810800 AN: 1456766 Hom.: 227839 Cov.: 37 AF XY: 0.560 AC XY: 405490 AN XY: 724696

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.659

Gnomad4 ASJ exome AF: 0.554

Gnomad4 EAS exome AF: 0.479

Gnomad4 SAS exome AF: 0.688

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.545

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.567 AC: 86120 AN: 151844 Hom.: 24558 Cov.: 32 AF XY: 0.570 AC XY: 42262 AN XY: 74196

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.482

Gnomad4 SAS AF: 0.695

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.554

Alfa AF: 0.559 Hom.: 17254

Bravo AF: 0.571

Asia WGS AF: 0.591 AC: 2047 AN: 3472

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	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+	-	- -

Autosomal dominant Parkinson disease 8 Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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	-0.58
CADD	Benign	8.3
DANN	Benign	0.62

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: rs11176013; hg19: chr12-40713873; COSMIC: COSV54153519; COSMIC: COSV54153519;