NM_198578.4:c.6324G>C

Variant names:

• chr12-40348452-G-C
• rs10878405
• NM_198578.4:c.6324G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198578.4(LRRK2):​c.6324G>C​(p.Glu2108Asp) 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. E2108E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.6324G>C	p.Glu2108Asp	missense_variant	Exon 43 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.6324G>C	p.Glu2108Asp	missense_variant	Exon 43 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.54	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.021	D
Polyphen		0.95	P
Vest4		0.33
MutPred		0.43		Loss of methylation at K2109 (P = 0.1406);
MVP		0.89
MPC		1.6
ClinPred		0.92	D
GERP RS		3.3
Varity_R		0.35
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;