rs1491942

Variant names:

• chr12-40227006-C-G
• rs1491942
• NM_198578.4:c.237+1366C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198578.4(LRRK2):​c.237+1366C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 151,852 control chromosomes in the GnomAD database, including 4,238 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4238 hom., cov: 31)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126
• Publications: 53 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.237+1366C>G		intron_variant	Intron 2 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.237+1366C>G		intron_variant	Intron 2 of 50	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34603 AN: 151736 Hom.: 4219 Cov.: 31

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.213

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34671 AN: 151852 Hom.: 4238 Cov.: 31 AF XY: 0.230 AC XY: 17043 AN XY: 74224

African (AFR) AF: 0.269 AC: 11119 AN: 41356

American (AMR) AF: 0.281 AC: 4292 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 699 AN: 3466

East Asian (EAS) AF: 0.358 AC: 1838 AN: 5130

South Asian (SAS) AF: 0.355 AC: 1706 AN: 4810

European-Finnish (FIN) AF: 0.114 AC: 1206 AN: 10572

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12991 AN: 67948

Other (OTH) AF: 0.211 AC: 445 AN: 2110

Alfa AF: 0.208 Hom.: 444

Bravo AF: 0.243

Asia WGS AF: 0.352 AC: 1221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.42
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1491942; hg19: chr12-40620808;