12-40363528-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

29 publications found

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 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

LRRK2 links:

ENSG00000258167 (HGNC:):

ENSG00000258167 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 39234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

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.7155A>G	p.Gly2385Gly	synonymous	Exon 48 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.7155A>G	p.Gly2385Gly	synonymous	Exon 48 of 51	ENSP00000298910.7
LRRK2	ENST00000430804.5	TSL:1	n.*3828A>G		non_coding_transcript_exon	Exon 27 of 30	ENSP00000410821.1
LRRK2	ENST00000430804.5	TSL:1	n.*3828A>G		3_prime_UTR	Exon 27 of 30	ENSP00000410821.1

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

GnomAD2 exomes

AF:

0.113

AC:

28221

AN:

250616

AF XY:

0.112

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 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

African (AFR)

AF:

0.0384

AC:

1281

AN:

33364

American (AMR)

AF:

0.0742

AC:

3304

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.0811

AC:

2110

AN:

26024

East Asian (EAS)

AF:

0.0164

AC:

648

AN:

39570

South Asian (SAS)

AF:

0.0364

AC:

3142

AN:

86220

European-Finnish (FIN)

AF:

0.243

AC:

12947

AN:

53344

Middle Eastern (MID)

AF:

0.0909

AC:

523

AN:

5752

European-Non Finnish (NFE)

AF:

0.148

AC:

163972

AN:

1110182

Other (OTH)

AF:

0.125

AC:

7538

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

7941

15881

23822

31762

39703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5696

11392

17088

22784

28480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.109

AC:

16586

AN:

151982

Hom.:

1252

Cov.:

AF XY:

0.111

AC XY:

8278

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0411

AC:

1704

AN:

41492

American (AMR)

AF:

0.0839

AC:

1279

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.0808

AC:

280

AN:

3464

East Asian (EAS)

AF:

0.0165

AC:

AN:

5162

South Asian (SAS)

AF:

0.0269

AC:

130

AN:

4824

European-Finnish (FIN)

AF:

0.256

AC:

2703

AN:

10574

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.147

AC:

9965

AN:

67910

Other (OTH)

AF:

0.101

AC:

212

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

710

1420

2130

2840

3550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.117

Hom.:

996

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

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

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

Aug 11, 2017

Athena Diagnostics

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

not specified

Benign:2

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.0

(source)

DANN

Benign

0.62

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over