rs1427263

Positions:

• chr12-40320032-C-A
• chr12-40320032-C-G
• chr12-40320032-C-T

Variant summary

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

The ENST00000298910.12(LRRK2):​c.4872C>A​(p.Gly1624=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,608,450 control chromosomes in the GnomAD database, including 361,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37378 hom., cov: 32)
  • Exomes 𝑓: 0.66 (323642 hom.)
• Consequence: LRRK2 ENST00000298910.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.535

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=-0.38).
• BP6: Variant 12-40320032-C-A is Benign according to our data. Variant chr12-40320032-C-A is described in ClinVar as [Benign]. Clinvar id is 39197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40320032-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.535 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.4872C>A	p.Gly1624=	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.4872C>A	p.Gly1624=	synonymous_variant	34/51	1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106016 AN: 151782 Hom.: 37343 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.673

GnomAD3 exomes AF: 0.679 AC: 169662 AN: 249798 Hom.: 58328 AF XY: 0.676 AC XY: 91378 AN XY: 135162

Gnomad AFR exome AF: 0.766

Gnomad AMR exome AF: 0.731

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.502

Gnomad SAS exome AF: 0.722

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.664 AC: 967676 AN: 1456552 Hom.: 323642 Cov.: 38 AF XY: 0.665 AC XY: 482154 AN XY: 724650

Gnomad4 AFR exome AF: 0.773

Gnomad4 AMR exome AF: 0.727

Gnomad4 ASJ exome AF: 0.612

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.772

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.670

GnomAD4 genome AF: 0.699 AC: 106109 AN: 151898 Hom.: 37378 Cov.: 32 AF XY: 0.705 AC XY: 52334 AN XY: 74258

Gnomad4 AFR AF: 0.770

Gnomad4 AMR AF: 0.713

Gnomad4 ASJ AF: 0.612

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.720

Gnomad4 FIN AF: 0.782

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.669

Alfa AF: 0.661 Hom.: 36855

Bravo AF: 0.691

Asia WGS AF: 0.633 AC: 2196 AN: 3474

EpiCase AF: 0.649

EpiControl AF: 0.644

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	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	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	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.6
DANN	Benign	0.65

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: rs1427263; hg19: chr12-40713834; COSMIC: COSV54146487;