rs11175964

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198578.4(LRRK2):c.4269G>A(p.Lys1423Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,646 control chromosomes in the GnomAD database, including 4,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 391 hom., cov: 32)

Exomes 𝑓: 0.069 ( 3898 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.22

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:

LRRK2 (HGNC:):

LRRK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-40309185-G-A is Benign according to our data. Variant chr12-40309185-G-A is described in ClinVar as [Benign]. Clinvar id is 39181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40309185-G-A is described in Lovd as [Likely_benign]. Variant chr12-40309185-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.4269G>A	p.Lys1423Lys	synonymous_variant	30/51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.4269G>A	p.Lys1423Lys	synonymous_variant	30/51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0603

AC:

9160

AN:

151992

Hom.:

391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.0916

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.0413

Gnomad FIN

AF:

0.0546

Gnomad MID

AF:

0.0732

Gnomad NFE

AF:

0.0686

Gnomad OTH

AF:

0.0738

GnomAD3 exomes

AF:

0.0746

AC:

18742

AN:

251084

Hom.:

877

AF XY:

0.0718

AC XY:

9743

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.0878

Gnomad EAS exome

AF:

0.0985

Gnomad SAS exome

AF:

0.0399

Gnomad FIN exome

AF:

0.0553

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.0690

GnomAD4 exome

AF:

0.0688

AC:

100604

AN:

1461536

Hom.:

3898

Cov.:

AF XY:

0.0678

AC XY:

49327

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.0158

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.0882

Gnomad4 EAS exome

AF:

0.120

Gnomad4 SAS exome

AF:

0.0392

Gnomad4 FIN exome

AF:

0.0564

Gnomad4 NFE exome

AF:

0.0684

Gnomad4 OTH exome

AF:

0.0691

GnomAD4 genome

AF:

0.0602

AC:

9158

AN:

152110

Hom.:

391

Cov.:

AF XY:

0.0612

AC XY:

4552

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0180

Gnomad4 AMR

AF:

0.128

Gnomad4 ASJ

AF:

0.0916

Gnomad4 EAS

AF:

0.0995

Gnomad4 SAS

AF:

0.0411

Gnomad4 FIN

AF:

0.0546

Gnomad4 NFE

AF:

0.0686

Gnomad4 OTH

AF:

0.0720

Alfa

AF:

0.0656

Hom.:

610

Bravo

AF:

0.0645

Asia WGS

AF:

0.0600

AC:

209

AN:

3478

EpiCase

AF:

0.0701

EpiControl

AF:

0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.1

DANN

Benign

0.56

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