NM_198578.4:c.6381+52G>A

Variant names:

• chr12-40348561-G-A
• rs11176143
• NM_198578.4:c.6381+52G>A

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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 9 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=-0.99).
• BP6: Variant 12-40348561-G-A is Benign according to our data. Variant chr12-40348561-G-A is described in ClinVar as Benign. ClinVar VariationId is 1238322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 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.6381+52G>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.6381+52G>A		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*3054+52G>A		intron	N/A	ENSP00000410821.1
	LRRK2	ENST00000680790.1		c.6126+52G>A		intron	N/A	ENSP00000505335.1

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

GnomAD2 exomes AF: 0.0969 AC: 18460 AN: 190470 AF XY: 0.101

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 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

African (AFR) AF: 0.0139 AC: 313 AN: 22466

American (AMR) AF: 0.0687 AC: 2733 AN: 39754

Ashkenazi Jewish (ASJ) AF: 0.0492 AC: 1107 AN: 22494

East Asian (EAS) AF: 0.109 AC: 3727 AN: 34346

South Asian (SAS) AF: 0.172 AC: 12025 AN: 69986

European-Finnish (FIN) AF: 0.128 AC: 6457 AN: 50298

Middle Eastern (MID) AF: 0.0799 AC: 272 AN: 3406

European-Non Finnish (NFE) AF: 0.0810 AC: 50125 AN: 618912

Other (OTH) AF: 0.0854 AC: 3541 AN: 41460

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

African (AFR) AF: 0.0188 AC: 781 AN: 41500

American (AMR) AF: 0.0900 AC: 1375 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3468

East Asian (EAS) AF: 0.113 AC: 582 AN: 5172

South Asian (SAS) AF: 0.196 AC: 942 AN: 4816

European-Finnish (FIN) AF: 0.126 AC: 1319 AN: 10500

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7180 AN: 67970

Other (OTH) AF: 0.0873 AC: 184 AN: 2108

Alfa AF: 0.100 Hom.: 1324

Bravo AF: 0.0751

Asia WGS AF: 0.131 AC: 455 AN: 3476

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

Aug 21, 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	-0.99
CADD	Benign	0.016
DANN	Benign	0.26
PhyloP100		-1.2
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: rs11176143; hg19: chr12-40742363;