rs10878258

Variant names:

• chr12-40247890-A-G
• rs10878258
• NM_198578.4:c.839-1936A>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.839-1936A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 151,054 control chromosomes in the GnomAD database, including 4,549 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 0.22 (4549 hom., cov: 30)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.403
• Publications: 6 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 (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.839-1936A>G		intron_variant	Intron 7 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.839-1936A>G		intron_variant	Intron 7 of 50	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33541 AN: 150952 Hom.: 4552 Cov.: 30

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.374

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.247

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

GnomAD4 genome AF: 0.222 AC: 33543 AN: 151054 Hom.: 4549 Cov.: 30 AF XY: 0.227 AC XY: 16734 AN XY: 73720

African (AFR) AF: 0.0748 AC: 3091 AN: 41304

American (AMR) AF: 0.229 AC: 3465 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1039 AN: 3470

East Asian (EAS) AF: 0.175 AC: 899 AN: 5146

South Asian (SAS) AF: 0.133 AC: 642 AN: 4812

European-Finnish (FIN) AF: 0.401 AC: 4102 AN: 10218

Middle Eastern (MID) AF: 0.365 AC: 105 AN: 288

European-Non Finnish (NFE) AF: 0.287 AC: 19422 AN: 67710

Other (OTH) AF: 0.250 AC: 522 AN: 2090

Alfa AF: 0.250 Hom.: 1468

Bravo AF: 0.205

Asia WGS AF: 0.150 AC: 526 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		0.40
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: rs10878258; hg19: chr12-40641692;