rs7966550

Positions:

• chr12-40294893-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.2857T>C​(p.Leu953=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,543,352 control chromosomes in the GnomAD database, including 9,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (796 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8999 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.974

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=-0.86).
• BP6: Variant 12-40294893-T-C is Benign according to our data. Variant chr12-40294893-T-C is described in ClinVar as [Benign]. Clinvar id is 39156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40294893-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.974 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.2857T>C	p.Leu953=	synonymous_variant	22/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.2857T>C	p.Leu953=	synonymous_variant	22/51	1	NM_198578.4	ENSP00000298910	P1
LRRK2	ENST00000680790.1	c.2602T>C	p.Leu868=	synonymous_variant	20/49			ENSP00000505335
LRRK2	ENST00000343742.6	c.2857T>C	p.Leu953=	synonymous_variant	22/27	5		ENSP00000341930
LRRK2	ENST00000679360.1	c.*1766T>C		3_prime_UTR_variant, NMD_transcript_variant	23/51			ENSP00000505368

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13926 AN: 151954 Hom.: 796 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.0820

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.104 AC: 26057 AN: 249754 Hom.: 1522 AF XY: 0.105 AC XY: 14239 AN XY: 135140

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.0625

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.109 AC: 151772 AN: 1391280 Hom.: 8999 Cov.: 24 AF XY: 0.108 AC XY: 75102 AN XY: 694816

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.0866

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.0610

Gnomad4 FIN exome AF: 0.0828

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.0916 AC: 13932 AN: 152072 Hom.: 796 Cov.: 32 AF XY: 0.0897 AC XY: 6669 AN XY: 74352

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.0820

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.110

Alfa AF: 0.118 Hom.: 1798

Bravo AF: 0.0940

Asia WGS AF: 0.102 AC: 355 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.60

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: rs7966550; hg19: chr12-40688695; COSMIC: COSV54147703; COSMIC: COSV54147703;