rs199566791

Variant names:

• chr12-40278154-A-G
• rs199566791
• NM_198578.4:c.2134A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198578.4(LRRK2):​c.2134A>G​(p.Met712Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M712T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.94
• Publications: 7 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

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.2134A>G	p.Met712Val	missense	Exon 18 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.2134A>G	p.Met712Val	missense	Exon 18 of 51	ENSP00000298910.7
	LRRK2	ENST00000680790.1		c.1879A>G	p.Met627Val	missense	Exon 16 of 49	ENSP00000505335.1
	LRRK2	ENST00000343742.6	TSL:5	c.2134A>G	p.Met712Val	missense	Exon 18 of 27	ENSP00000341930.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	-	Autosomal dominant Parkinson disease 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.022	D
Polyphen		0.28	B
Vest4		0.87
MutPred		0.80		Loss of helix (P = 0.0237)
MVP		0.82
MPC		0.11
ClinPred		0.73	D
GERP RS		2.0
Varity_R		0.19
gMVP		0.38
Mutation Taster		=37/63	disease causing

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: rs199566791; hg19: chr12-40671956;