chr12-40313976-G-A

Position:

• chr12-40313976-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 5.84

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 -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	c.4541G>A	p.Arg1514Gln	missense_variant	32/51	ENST00000298910.12	NP_940980.4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 687 AN: 151802 Hom.: 1 Cov.: 32

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.: 3 AF XY: 0.00399 AC XY: 538 AN XY: 134768

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.: 59 Cov.: 31 AF XY: 0.00691 AC XY: 5012 AN XY: 725490

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.: 1 Cov.: 32 AF XY: 0.00432 AC XY: 321 AN XY: 74264

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.: 4

Bravo AF: 0.00395

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00687 AC: 59

ExAC AF: 0.00373 AC: 453

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00753

EpiControl AF: 0.00647

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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 Parkinson’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 variant’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:3 Other: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	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.52	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.10
Sift	Benign	0.36	T
Sift4G	Benign	0.81	T
Polyphen		0.58	P
Vest4		0.39
MVP		0.83
MPC		0.21
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs35507033; hg19: chr12-40707778; COSMIC: COSV104599173;