rs41286468

Variant names:

• chr12-40235642-C-G
• rs41286468
• NM_198578.4:c.364C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-40235642-C-G
• chr12-40235642-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198578.4(LRRK2):​c.364C>G​(p.Leu122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L122L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 0 publications found

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]

LRRK2 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.364C>G	p.Leu122Val	missense	Exon 4 of 51	NP_940980.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.364C>G	p.Leu122Val	missense	Exon 4 of 51	ENSP00000298910.7
	LRRK2	ENST00000680790.1		c.364C>G	p.Leu122Val	missense	Exon 4 of 49	ENSP00000505335.1
	LRRK2	ENST00000343742.6	TSL:5	c.364C>G	p.Leu122Val	missense	Exon 4 of 27	ENSP00000341930.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.31
Sift	Benign	0.48	T
Sift4G	Benign	0.21	T
Polyphen		0.96	D
Vest4		0.46
MutPred		0.65		Gain of sheet (P = 0.0507)
MVP		0.84
MPC		0.30
ClinPred		0.96	D
GERP RS		2.9
Varity_R		0.13
gMVP		0.34
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs41286468; hg19: chr12-40629444;