rs10784486

Variant names:

• chr12-40283227-A-C
• rs10784486
• NM_198578.4:c.2242-648A>C

Variant summary

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

The NM_198578.4(LRRK2):​c.2242-648A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 151,994 control chromosomes in the GnomAD database, including 37,802 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 0.70 (37802 hom., cov: 31)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 11 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.2242-648A>C		intron_variant	Intron 18 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.2242-648A>C		intron_variant	Intron 18 of 50	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106849 AN: 151876 Hom.: 37768 Cov.: 31

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.688

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

GnomAD4 genome AF: 0.704 AC: 106938 AN: 151994 Hom.: 37802 Cov.: 31 AF XY: 0.709 AC XY: 52694 AN XY: 74282

African (AFR) AF: 0.746 AC: 30907 AN: 41458

American (AMR) AF: 0.722 AC: 11019 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 2190 AN: 3468

East Asian (EAS) AF: 0.515 AC: 2644 AN: 5138

South Asian (SAS) AF: 0.728 AC: 3505 AN: 4816

European-Finnish (FIN) AF: 0.791 AC: 8356 AN: 10566

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 46031 AN: 67970

Other (OTH) AF: 0.684 AC: 1445 AN: 2112

Alfa AF: 0.681 Hom.: 98256

Bravo AF: 0.696

Asia WGS AF: 0.632 AC: 2195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	7.3
DANN	Benign	0.81
PhyloP100		0.20
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: rs10784486; hg19: chr12-40677029;