12-40225177-C-A

Variant names:

• chr12-40225177-C-A
• NM_198578.4:c.46C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198578.4(LRRK2):​c.46C>A​(p.Leu16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.390

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27251005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.46C>A	p.Leu16Met	missense_variant	Exon 1 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.46C>A	p.Leu16Met	missense_variant	Exon 1 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L16M variant (also known as c.46C>A), located in coding exon 1 of the LRRK2 gene, results from a C to A substitution at nucleotide position 46. The leucine at codon 16 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	.;D
Vest4		0.35
MutPred		0.31		Loss of methylation at K17 (P = 0.0494);Loss of methylation at K17 (P = 0.0494);
MVP		0.79
MPC		0.44
ClinPred		0.88	D
GERP RS		3.1
Varity_R		0.38
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-40618979; COSMIC: COSV54177303; COSMIC: COSV54177303;