rs17466213

Positions:

• chr12-40308618-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_198578.4(LRRK2):​c.4111A>G​(p.Ile1371Val) variant causes a missense change. The variant allele was found at a frequency of 0.000808 in 1,614,078 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (5 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 5.25

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 Benign. Variant got -14 ACMG points.

• PM1: In a domain Roc (size 183) in uniprot entity LRRK2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_198578.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.017168522).
• BP6: Variant 12-40308618-A-G is Benign according to our data. Variant chr12-40308618-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 39176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40308618-A-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd4 at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.4111A>G	p.Ile1371Val	missense_variant	29/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.4111A>G	p.Ile1371Val	missense_variant	29/51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000865 AC: 217 AN: 250952 Hom.: 1 AF XY: 0.00105 AC XY: 142 AN XY: 135610

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000824 AC: 1204 AN: 1461724 Hom.: 5 Cov.: 31 AF XY: 0.000891 AC XY: 648 AN XY: 727162

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00412

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000666

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74494

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000537 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	LRRK2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.42	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.45
Sift	Benign	0.44	T
Sift4G	Benign	0.15	T
Polyphen		0.29	B
Vest4		0.76
MPC		0.43
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.52

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: rs17466213; hg19: chr12-40702420;