chr12-40363528-A-G

Variant names:

Variant summary

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

The NM_198578.4(LRRK2):c.7155A>G(p.Gly2385Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,611,208 control chromosomes in the GnomAD database, including 16,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1252 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14824 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.34

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:

LOC105369736 (HGNC:):

LOC105369736 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 12-40363528-A-G is Benign according to our data. Variant chr12-40363528-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 39234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40363528-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.7155A>G	p.Gly2385Gly	synonymous_variant	Exon 48 of 51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.7155A>G	p.Gly2385Gly	synonymous_variant	Exon 48 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16574

AN:

151864

Hom.:

1250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0408

Gnomad AMI

AF:

0.219

Gnomad AMR

AF:

0.0841

Gnomad ASJ

AF:

0.0808

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.102

GnomAD3 exomes

AF:

0.113

AC:

28221

AN:

250616

Hom.:

2177

AF XY:

0.112

AC XY:

15158

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.0376

Gnomad AMR exome

AF:

0.0745

Gnomad ASJ exome

AF:

0.0810

Gnomad EAS exome

AF:

0.0170

Gnomad SAS exome

AF:

0.0368

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.147

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.134

AC:

195465

AN:

1459226

Hom.:

14824

Cov.:

AF XY:

0.132

AC XY:

95495

AN XY:

725966

show subpopulations

Gnomad4 AFR exome

AF:

0.0384

Gnomad4 AMR exome

AF:

0.0742

Gnomad4 ASJ exome

AF:

0.0811

Gnomad4 EAS exome

AF:

0.0164

Gnomad4 SAS exome

AF:

0.0364

Gnomad4 FIN exome

AF:

0.243

Gnomad4 NFE exome

AF:

0.148

Gnomad4 OTH exome

AF:

0.125

GnomAD4 genome

AF:

0.109

AC:

16586

AN:

151982

Hom.:

1252

Cov.:

AF XY:

0.111

AC XY:

8278

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0411

Gnomad4 AMR

AF:

0.0839

Gnomad4 ASJ

AF:

0.0808

Gnomad4 EAS

AF:

0.0165

Gnomad4 SAS

AF:

0.0269

Gnomad4 FIN

AF:

0.256

Gnomad4 NFE

AF:

0.147

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.124

Hom.:

833

Bravo

AF:

0.0949

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

EpiCase

AF:

0.140

EpiControl

AF:

0.139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Sep 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 11, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.0

DANN

Benign

0.62

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