rs281865047

Positions:

• chr12-40302866-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_198578.4(LRRK2):​c.3574A>G​(p.Ile1192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000252 in 1,587,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 3.40

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19814435).
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.3574A>G	p.Ile1192Val	missense_variant	26/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.3574A>G	p.Ile1192Val	missense_variant	26/51	1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000680 AC: 17 AN: 249918 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000244 AC: 35 AN: 1435782 Hom.: 0 Cov.: 27 AF XY: 0.0000223 AC XY: 16 AN XY: 715936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1192 of the LRRK2 protein (p.Ile1192Val). This variant is present in population databases (rs281865047, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson's disease (PMID: 17804834). ClinVar contains an entry for this variant (Variation ID: 39168). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect LRRK2 function (PMID: 20642453). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.21
Sift	Benign	0.32	T;T
Sift4G	Benign	0.069	T;T
Polyphen		0.82	P;P
Vest4		0.73
MVP		0.78
MPC		0.074
ClinPred		0.079	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.18

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: rs281865047; hg19: chr12-40696668;