rs34805604

chr12-40299125-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_198578.4(LRRK2):c.3364A>G(p.Ile1122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.30

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-40299125-A-G is Pathogenic according to our data. Variant chr12-40299125-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1939.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.3364A>G	p.Ile1122Val	missense_variant	25/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.3364A>G	p.Ile1122Val	missense_variant	25/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461130 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000598 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 18, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	8.9
Dann	Benign	0.69
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0057	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.024	A;A
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.24
Sift	Benign	0.064	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.0080	B;B
Vest4		0.17
MutPred		0.65		Gain of ubiquitination at K1118 (P = 0.0804);Gain of ubiquitination at K1118 (P = 0.0804);
MVP		0.61
MPC		0.072
ClinPred		0.14	T
GERP RS		3.8
Varity_R		0.083
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34805604; hg19: chr12-40692927;