12-40287461-A-G

Position:

• chr12-40287461-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_198578.4(LRRK2):​c.2611A>G​(p.Lys871Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,760 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 3.53

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4162493).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.2611A>G	p.Lys871Glu	missense_variant	20/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.2611A>G	p.Lys871Glu	missense_variant	20/51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250860 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460840 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726714

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74210

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

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	Jul 13, 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. 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. ClinVar contains an entry for this variant (Variation ID: 39152). This variant has not been reported in the literature in individuals affected with LRRK2-related conditions. This variant is present in population databases (rs281865044, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 871 of the LRRK2 protein (p.Lys871Glu). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.21
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.014	D;T
Polyphen		0.98	D;B
Vest4		0.60
MutPred		0.32		Loss of methylation at K871 (P = 0.0067);Loss of methylation at K871 (P = 0.0067);
MVP		0.85
MPC		0.26
ClinPred		0.31	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.38

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: rs281865044; hg19: chr12-40681263;