rs10878405

chr12-40348452-G-Achr12-40348452-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):c.6324G>A(p.Glu2108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,607,610 control chromosomes in the GnomAD database, including 80,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6173 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73852 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 3.27

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-40348452-G-A is Benign according to our data. Variant chr12-40348452-G-A is described in ClinVar as [Benign]. Clinvar id is 39222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40348452-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.6324G>A	p.Glu2108=	synonymous_variant	43/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.6324G>A	p.Glu2108=	synonymous_variant	43/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41286 AN: 151872 Hom.: 6171 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.264

GnomAD3 exomes AF: 0.302 AC: 75665 AN: 250916 Hom.: 12165 AF XY: 0.309 AC XY: 41856 AN XY: 135602

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.313 AC: 456015 AN: 1455620 Hom.: 73852 Cov.: 32 AF XY: 0.315 AC XY: 228474 AN XY: 724384

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.320

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.381

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.272 AC: 41305 AN: 151990 Hom.: 6173 Cov.: 33 AF XY: 0.278 AC XY: 20613 AN XY: 74274

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.266

Alfa AF: 0.301 Hom.: 9463

Bravo AF: 0.253

Asia WGS AF: 0.337 AC: 1167 AN: 3472

EpiCase AF: 0.305

EpiControl AF: 0.310

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 specified Benign:3

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	6.6
Dann	Benign	0.56

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: rs10878405; hg19: chr12-40742254; COSMIC: COSV54147530;