rs201739149

Positions:

• chr12-40302773-AT-A
• chr12-40302773-AT-ATT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000298910.12(LRRK2):​c.3497-8del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,518,106 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (20 hom.)
• Consequence: LRRK2 ENST00000298910.12 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.158

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 -16 ACMG points.

• BP6: Variant 12-40302773-AT-A is Benign according to our data. Variant chr12-40302773-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 308626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1863/151728) while in subpopulation AFR AF= 0.0392 (1624/41432). AF 95% confidence interval is 0.0376. There are 51 homozygotes in gnomad4. There are 863 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1863 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.3497-8del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.3497-8del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1862 AN: 151612 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00934

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000708

Gnomad OTH AF: 0.0121

GnomAD3 exomes AF: 0.00358 AC: 881 AN: 245896 Hom.: 10 AF XY: 0.00284 AC XY: 380 AN XY: 133730

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00414

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00192 AC: 2620 AN: 1366378 Hom.: 20 Cov.: 24 AF XY: 0.00173 AC XY: 1188 AN XY: 685484

Gnomad4 AFR exome AF: 0.0401

Gnomad4 AMR exome AF: 0.00330

Gnomad4 ASJ exome AF: 0.00439

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.0000943

Gnomad4 NFE exome AF: 0.000750

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome AF: 0.0123 AC: 1863 AN: 151728 Hom.: 51 Cov.: 32 AF XY: 0.0116 AC XY: 863 AN XY: 74180

Gnomad4 AFR AF: 0.0392

Gnomad4 AMR AF: 0.00933

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000708

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.0145

Asia WGS AF: 0.00145 AC: 5 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 19, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	This variant is associated with the following publications: (PMID: 25980689) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2018	- -

LRRK2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs201739149; hg19: chr12-40696575;