rs41286460

Variant names:

• chr12-40323151-A-G
• rs41286460
• NM_198578.4:c.5510-9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198578.4(LRRK2):​c.5510-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,610,342 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (19 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Scores: Splicing: ADA: 0.00002014
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.11
• Publications: 3 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: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Parkinson disease

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-40323151-A-G is Benign according to our data. Variant chr12-40323151-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00322 (4693/1458164) while in subpopulation MID AF = 0.0179 (103/5756). AF 95% confidence interval is 0.0151. There are 19 homozygotes in GnomAdExome4. There are 2377 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 401 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.5510-9A>G		intron	N/A	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.5510-9A>G		intron	N/A	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*2183-9A>G		intron	N/A	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000950031.1		c.5486-9A>G		intron	N/A	ENSP00000620090.1

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 152060 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00396

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00281 AC: 704 AN: 250682 AF XY: 0.00306

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00716

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00322 AC: 4693 AN: 1458164 Hom.: 19 Cov.: 30 AF XY: 0.00328 AC XY: 2377 AN XY: 725500

African (AFR) AF: 0.000809 AC: 27 AN: 33394

American (AMR) AF: 0.00222 AC: 99 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00832 AC: 217 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00294 AC: 253 AN: 85956

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53368

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5756

European-Non Finnish (NFE) AF: 0.00340 AC: 3770 AN: 1109148

Other (OTH) AF: 0.00317 AC: 191 AN: 60232

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152178 Hom.: 2 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74390

African (AFR) AF: 0.00101 AC: 42 AN: 41560

American (AMR) AF: 0.00229 AC: 35 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00396 AC: 269 AN: 67934

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00385 Hom.: 1

Bravo AF: 0.00243

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.00360

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (3)
-	-	2	not provided (2)
-	-	1	LRRK2-related disorder (1)
-	-	1	not specified (1)
-	-	1	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.067
DANN	Benign	0.41
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.010
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: rs41286460; hg19: chr12-40716953;