rs60545352

chr12-40364884-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_198578.4(LRRK2):c.7224G>A(p.Met2408Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2408K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 1.40

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]

LOC105369736 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a mutagenesis_site No effect on WD domain homodimerization. No effect on kinase activity. (size 0) in uniprot entity LRRK2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.10231966).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.7224G>A	p.Met2408Ile	missense_variant	49/51	ENST00000298910.12
LOC105369736	XR_944868.3	n.485-10057C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.7224G>A	p.Met2408Ile	missense_variant	49/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151894 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.000480

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250234 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460252 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 726446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151894 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74194

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000657

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: 0.000480

Alfa AF: 0.0000334 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The LRRK2 p.Met2408Ile variant was not identified in Clinvitae, Cosmic, MutDB and LOVD 3.0. The variant was identified in dbSNP (ID: rs60545352) and in ClinVar (classified as a VUS for Parkinson disease 8, autosomal dominant by GeneReviews). The variant was also identified in control databases in 6 of 281598 chromosomes at a frequency of 0.000021 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7162 chromosomes (freq: 0.00014), Latino in 3 of 35242 chromosomes (freq: 0.000085), European (non-Finnish) in 2 of 128360 chromosomes (freq: 0.000016), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. In a study analyzing LRRK2 variants in patients with familial Parkinson's disease, the p.Met2408Ile variant was identified in one proband with familial PD, but was also found in an unaffected individual from another family and in two healthy control subjects, suggesting this variant does not segregate with disease (Jasinska-Myga_2010_PMID: 20721913). The variant is located in the WD40 protein domain (O.A. Ross_2011_PMID: 21885347), however the p.Met2408 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Autosomal dominant Parkinson disease 8 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.053
Sift	Benign	0.50	T
Sift4G	Benign	0.34	T
Polyphen		0.014	B
Vest4		0.17
MutPred		0.24		Loss of sheet (P = 0.0054);
MVP		0.79
MPC		0.22
ClinPred		0.042	T
GERP RS		3.5
Varity_R		0.26
gMVP		0.34

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: rs60545352; hg19: chr12-40758686;