12-40346563-G-T

Variant names:

• chr12-40346563-G-T
• rs10784522
• NM_198578.4:c.6110-190G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.6110-190G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,878 control chromosomes in the GnomAD database, including 7,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.31 (7274 hom., cov: 32)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.938
• Publications: 4 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

ENSG00000258167 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-40346563-G-T is Benign according to our data. Variant chr12-40346563-G-T is described in ClinVar as Benign. ClinVar VariationId is 1257037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 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.6110-190G>T		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.6110-190G>T		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*2783-190G>T		intron	N/A	ENSP00000410821.1
	LRRK2	ENST00000680790.1		c.5855-190G>T		intron	N/A	ENSP00000505335.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46312 AN: 151760 Hom.: 7272 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.288

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

GnomAD4 genome AF: 0.305 AC: 46330 AN: 151878 Hom.: 7274 Cov.: 32 AF XY: 0.310 AC XY: 23006 AN XY: 74222

African (AFR) AF: 0.254 AC: 10502 AN: 41410

American (AMR) AF: 0.281 AC: 4296 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3466

East Asian (EAS) AF: 0.341 AC: 1765 AN: 5172

South Asian (SAS) AF: 0.368 AC: 1771 AN: 4814

European-Finnish (FIN) AF: 0.391 AC: 4121 AN: 10528

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22083 AN: 67908

Other (OTH) AF: 0.290 AC: 610 AN: 2106

Alfa AF: 0.227 Hom.: 593

Bravo AF: 0.291

Asia WGS AF: 0.345 AC: 1197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 05, 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	-0.89
CADD	Benign	1.6
DANN	Benign	0.11
PhyloP100		-0.94
PromoterAI		0.0078	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs10784522; hg19: chr12-40740365;