Variant chr12-40302773-AT-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.158

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	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.:

Cov.:

show subpopulations

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.:

AF XY:

0.00284

AC XY:

380

AN XY:

133730

show subpopulations

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.:

Cov.:

AF XY:

0.00173

AC XY:

1188

AN XY:

685484

show subpopulations

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.:

Cov.:

AF XY:

0.0116

AC XY:

863

AN XY:

74180

show subpopulations

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.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00145

AC:

AN:

3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over