rs35507033

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198578.4(LRRK2):c.4541G>A(p.Arg1514Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00695 in 1,609,956 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 59 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 5.84

Variant links:

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 links:

LRRK2 (HGNC:):

LRRK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009949774).

BP6

Variant 12-40313976-G-A is Benign according to our data. Variant chr12-40313976-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 39191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40313976-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00452 (686/151920) while in subpopulation NFE AF= 0.0076 (516/67932). AF 95% confidence interval is 0.00705. There are 1 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 686 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.4541G>A	p.Arg1514Gln	missense_variant	32/51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.4541G>A	p.Arg1514Gln	missense_variant	32/51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.00453

AC:

687

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00388

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00456

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00761

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00400

AC:

996

AN:

248880

Hom.:

AF XY:

0.00399

AC XY:

538

AN XY:

134768

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00213

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00367

Gnomad NFE exome

AF:

0.00688

Gnomad OTH exome

AF:

0.00528

GnomAD4 exome

AF:

0.00720

AC:

10496

AN:

1458036

Hom.:

Cov.:

AF XY:

0.00691

AC XY:

5012

AN XY:

725490

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00392

Gnomad4 NFE exome

AF:

0.00868

Gnomad4 OTH exome

AF:

0.00751

GnomAD4 genome

AF:

0.00452

AC:

686

AN:

151920

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

321

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.00387

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00456

Gnomad4 NFE

AF:

0.00760

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00671

Hom.:

Bravo

AF:

0.00395

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00687

AC:

ExAC

AF:

0.00373

AC:

453

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00753

EpiControl

AF:

0.00647

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The LRRK2 p.Arg1514Gln variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs35507033), ClinVar (classified as Benign by Invitae; associated condition is autosomal dominant Parkinson disease 8), and LOVD 3.0. The variant was also identified in control databases in 1161 of 280242 chromosomes (3 homozygous) at a frequency of 0.004143 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: European (non-Finnish) in 901 of 128130 chromosomes (freq: 0.007032), Other in 36 of 7142 chromosomes (freq: 0.005041), European (Finnish) in 93 of 24168 chromosomes (freq: 0.003848), Latino in 75 of 35192 chromosomes (freq: 0.002131), Ashkenazi Jewish in 19 of 10328 chromosomes (freq: 0.00184), African in 36 of 24800 chromosomes (freq: 0.001452) and South Asian in 1 of 30568 chromosomes (freq: 0.000033), while the variant was not observed in the East Asian population. One study demonstrated the R1514Q variant did not segregate fully with Parkinsonâ€šÃ„Ã´s disease. Combined analyses of three case-control series showed the R1514Q substitution was not associated with increased risk of disease (Toft_2007_PMID:17216639). Another study explored the variantâ€šÃ„Ã´s pathogenicity by studying populations carrying the mutation and the data suggested that the p.R1514Q variant is not a pathogenic mutation (Nichols_2006_PMID:17149721). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg1514 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 16172858, 17149721, 20721913, 24488318, 21885347, 17200152, 20642453, 25466404, 17216639, 24082139) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LRRK2: BP4, BS1, BS2 -

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 09, 2021	- -

LRRK2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.025

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.013

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.52

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.68

REVEL

Benign

0.10

Sift

Benign

0.36

Sift4G

Benign

0.81

Polyphen

0.58

Vest4

0.39

MVP

0.83

MPC

0.21

ClinPred

0.012

GERP RS

5.0

Varity_R

0.25

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over