rs33995883

chr12-40346884-A-Gchr12-40346884-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):c.6241A>G(p.Asn2081Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0168 in 1,612,916 control chromosomes in the GnomAD database, including 379 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2081I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.017 (356 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 7.19

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain Protein kinase (size 259) in uniprot entity LRRK2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_198578.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.00891602).
• BP6: Variant 12-40346884-A-G is Benign according to our data. Variant chr12-40346884-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 39221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40346884-A-G is described in Lovd as [Benign]. Variant chr12-40346884-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.6241A>G	p.Asn2081Asp	missense_variant	42/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.6241A>G	p.Asn2081Asp	missense_variant	42/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2067 AN: 152194 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0176 AC: 4406 AN: 250168 Hom.: 97 AF XY: 0.0190 AC XY: 2572 AN XY: 135226

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00956

Gnomad ASJ exome AF: 0.0608

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0322

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0171 AC: 25013 AN: 1460604 Hom.: 356 Cov.: 31 AF XY: 0.0178 AC XY: 12935 AN XY: 726576

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.0552

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0338

Gnomad4 FIN exome AF: 0.00414

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0136 AC: 2066 AN: 152312 Hom.: 23 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74486

Gnomad4 AFR AF: 0.00332

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0524

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0329

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0202 Hom.: 80

Bravo AF: 0.0130

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0191 AC: 164

ExAC AF: 0.0175 AC: 2118

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0263

EpiControl AF: 0.0237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	This variant is associated with the following publications: (PMID: 32677286, 29795570, 29321258, 25378673) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.13	N
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.081	T
Sift4G	Uncertain	0.035	D
Polyphen		0.39	B
Vest4		0.19
MPC		1.9
ClinPred		0.015	T
GERP RS		5.6
Varity_R		0.46
gMVP		0.43

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: rs33995883; hg19: chr12-40740686;