rs35870237

chr12-40340404-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_198578.4(LRRK2):c.6059T>C(p.Ile2020Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2020V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.75

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 7) in uniprot entity LRRK2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_198578.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 12-40340404-T-C is Pathogenic according to our data. Variant chr12-40340404-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1941.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-40340404-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.6059T>C	p.Ile2020Thr	missense_variant	41/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.6059T>C	p.Ile2020Thr	missense_variant	41/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000251 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.93
MutPred		0.85		Loss of stability (P = 0.0021);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs35870237; hg19: chr12-40734206;