rs11176143

Positions:

• chr12-40348561-G-A
• chr12-40348561-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198578.4(LRRK2):​c.6381+52G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 1,055,146 control chromosomes in the GnomAD database, including 5,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.083 (703 hom., cov: 32)
  • Exomes 𝑓: 0.089 (4846 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 12-40348561-G-A is Benign according to our data. Variant chr12-40348561-G-A is described in ClinVar as [Benign]. Clinvar id is 1238322.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.6381+52G>A		intron_variant		ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.6381+52G>A		intron_variant		1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0830 AC: 12606 AN: 151906 Hom.: 704 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0902

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0872

GnomAD3 exomes AF: 0.0969 AC: 18460 AN: 190470 Hom.: 1189 AF XY: 0.101 AC XY: 10322 AN XY: 102234

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0653

Gnomad ASJ exome AF: 0.0487

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.0911

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0889 AC: 80300 AN: 903122 Hom.: 4846 Cov.: 12 AF XY: 0.0934 AC XY: 43700 AN XY: 468090

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0687

Gnomad4 ASJ exome AF: 0.0492

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.0810

Gnomad4 OTH exome AF: 0.0854

GnomAD4 genome AF: 0.0829 AC: 12598 AN: 152024 Hom.: 703 Cov.: 32 AF XY: 0.0862 AC XY: 6406 AN XY: 74300

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.0900

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0873

Alfa AF: 0.101 Hom.: 1171

Bravo AF: 0.0751

Asia WGS AF: 0.131 AC: 455 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.016
DANN	Benign	0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs11176143; hg19: chr12-40742363;