12-40251828-G-A

Variant names:

• chr12-40251828-G-A
• rs1491938
• NM_198578.4:c.1181+284G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198578.4(LRRK2):​c.1181+284G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 151,980 control chromosomes in the GnomAD database, including 18,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.48 (18236 hom., cov: 31)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0760
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-40251828-G-A is Benign according to our data. Variant chr12-40251828-G-A is described in ClinVar as Benign. ClinVar VariationId is 1250049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.1181+284G>A		intron	N/A	NP_940980.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.1181+284G>A		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000680790.1		c.1181+284G>A		intron	N/A	ENSP00000505335.1
	LRRK2	ENST00000343742.6	TSL:5	c.1181+284G>A		intron	N/A	ENSP00000341930.2

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72464 AN: 151860 Hom.: 18226 Cov.: 31

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.465

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

GnomAD4 genome AF: 0.477 AC: 72504 AN: 151980 Hom.: 18236 Cov.: 31 AF XY: 0.471 AC XY: 34979 AN XY: 74262

African (AFR) AF: 0.337 AC: 13959 AN: 41476

American (AMR) AF: 0.381 AC: 5818 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1681 AN: 3464

East Asian (EAS) AF: 0.356 AC: 1837 AN: 5166

South Asian (SAS) AF: 0.616 AC: 2971 AN: 4820

European-Finnish (FIN) AF: 0.493 AC: 5203 AN: 10550

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39453 AN: 67932

Other (OTH) AF: 0.465 AC: 983 AN: 2114

Alfa AF: 0.538 Hom.: 54156

Bravo AF: 0.458

Asia WGS AF: 0.464 AC: 1608 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.46
DANN	Benign	0.63
PhyloP100		-0.076
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: rs1491938; hg19: chr12-40645630;