12-40320099-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198578.4(LRRK2):c.4939T>A(p.Ser1647Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,609,436 control chromosomes in the GnomAD database, including 74,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1647S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.27 ( 5907 hom., cov: 32)

Exomes 𝑓: 0.30 ( 68380 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.829

Publications

97 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012919903).

BP6

Variant 12-40320099-T-A is Benign according to our data. Variant chr12-40320099-T-A is described in ClinVar as Benign. ClinVar VariationId is 39201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4939T>A	p.Ser1647Thr	missense_variant	Exon 34 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.4939T>A	p.Ser1647Thr	missense_variant	Exon 34 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41281

AN:

151744

Hom.:

5906

Cov.:

show subpopulations

Gnomad AFR

AF:

0.182

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.246

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.372

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.259

GnomAD2 exomes

AF:

0.298

AC:

74234

AN:

249470

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.206

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.371

Gnomad NFE exome

AF:

0.304

Gnomad OTH exome

AF:

0.297

GnomAD4 exome

AF:

0.302

AC:

440219

AN:

1457574

Hom.:

68380

Cov.:

AF XY:

0.304

AC XY:

220692

AN XY:

725254

show subpopulations

African (AFR)

AF:

0.179

AC:

5965

AN:

33320

American (AMR)

AF:

0.212

AC:

9443

AN:

44514

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

7135

AN:

26022

East Asian (EAS)

AF:

0.321

AC:

12704

AN:

39570

South Asian (SAS)

AF:

0.365

AC:

31327

AN:

85916

European-Finnish (FIN)

AF:

0.368

AC:

19638

AN:

53348

Middle Eastern (MID)

AF:

0.242

AC:

1392

AN:

5750

European-Non Finnish (NFE)

AF:

0.302

AC:

334597

AN:

1108902

Other (OTH)

AF:

0.299

AC:

18018

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

15095

30191

45286

60382

75477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10852

21704

32556

43408

54260

<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:

0.272

AC:

41295

AN:

151862

Hom.:

5907

Cov.:

AF XY:

0.276

AC XY:

20450

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.182

AC:

7555

AN:

41474

American (AMR)

AF:

0.246

AC:

3744

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

951

AN:

3466

East Asian (EAS)

AF:

0.340

AC:

1751

AN:

5156

South Asian (SAS)

AF:

0.371

AC:

1786

AN:

4812

European-Finnish (FIN)

AF:

0.361

AC:

3801

AN:

10540

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.308

AC:

20899

AN:

67876

Other (OTH)

AF:

0.260

AC:

547

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1552

3103

4655

6206

7758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.300

Hom.:

5361

Bravo

AF:

0.256

TwinsUK

AF:

0.302

AC:

1119

ALSPAC

AF:

0.304

AC:

1172

ESP6500AA

AF:

0.179

AC:

787

ESP6500EA

AF:

0.298

AC:

2561

ExAC

AF:

0.296

AC:

35962

Asia WGS

AF:

0.340

AC:

1177

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Mar 06, 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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30917570, 23842774, 20629711, 20721913, 31085292, 20186690, 26311745) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.5

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.17

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.39

PhyloP100

0.83

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.15

REVEL

Benign

0.086

Sift

Benign

0.95

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.037

MPC

0.078

ClinPred

0.00020

GERP RS

0.45

Varity_R

0.093

gMVP

0.15

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over