12-40258718-T-C

Variant names:

• chr12-40258718-T-C
• rs2723264
• NM_198578.4:c.1419-762T>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.1419-762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 152,114 control chromosomes in the GnomAD database, including 49,938 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 0.81 (49938 hom., cov: 31)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.276
• Publications: 12 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.1419-762T>C		intron_variant	Intron 12 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.1419-762T>C		intron_variant	Intron 12 of 50	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123132 AN: 151996 Hom.: 49903 Cov.: 31

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.788

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

GnomAD4 genome AF: 0.810 AC: 123221 AN: 152114 Hom.: 49938 Cov.: 31 AF XY: 0.815 AC XY: 60585 AN XY: 74354

African (AFR) AF: 0.780 AC: 32361 AN: 41496

American (AMR) AF: 0.844 AC: 12888 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2611 AN: 3472

East Asian (EAS) AF: 0.837 AC: 4310 AN: 5152

South Asian (SAS) AF: 0.862 AC: 4155 AN: 4822

European-Finnish (FIN) AF: 0.889 AC: 9422 AN: 10596

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54852 AN: 67988

Other (OTH) AF: 0.785 AC: 1657 AN: 2112

Alfa AF: 0.805 Hom.: 207651

Bravo AF: 0.804

Asia WGS AF: 0.861 AC: 2990 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.93
DANN	Benign	0.39
PhyloP100		-0.28
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: rs2723264; hg19: chr12-40652520;