12-40310435-G-C

Variant names:

• chr12-40310435-G-C
• rs34995376
• NM_198578.4:c.4322G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_198578.4(LRRK2):​c.4322G>C​(p.Arg1441Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R1441H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47
• 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: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Parkinson disease

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_198578.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-40310435-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.4322G>C	p.Arg1441Pro	missense	Exon 31 of 51	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.4322G>C	p.Arg1441Pro	missense	Exon 31 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*995G>C		non_coding_transcript_exon	Exon 10 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*995G>C		3_prime_UTR	Exon 10 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant Parkinson disease 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Benign	0.20	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.78		Loss of MoRF binding (P = 0.0152)
MVP		0.95
MPC		0.56
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.034	Neutral
Varity_R		0.98
gMVP		0.88
Mutation Taster		=20/80	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: rs34995376; hg19: chr12-40704237;