rs11564148

Positions:

chr12-40320099-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000298910.12(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. 15/20 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
ENST00000298910.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.829

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 -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 id is 39201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40320099-T-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.4939T>A	p.Ser1647Thr	missense_variant	34/51	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.4939T>A	p.Ser1647Thr	missense_variant	34/51	1	NM_198578.4	ENSP00000298910	P1

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

GnomAD3 exomes

AF:

0.298

AC:

74234

AN:

249470

Hom.:

11750

AF XY:

0.304

AC XY:

41010

AN XY:

135114

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 SAS exome

AF:

0.369

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

Gnomad4 AFR exome

AF:

0.179

Gnomad4 AMR exome

AF:

0.212

Gnomad4 ASJ exome

AF:

0.274

Gnomad4 EAS exome

AF:

0.321

Gnomad4 SAS exome

AF:

0.365

Gnomad4 FIN exome

AF:

0.368

Gnomad4 NFE exome

AF:

0.302

Gnomad4 OTH exome

AF:

0.299

GnomAD4 genome

AF:

0.272

AC:

41295

AN:

151862

Hom.:

5907

Cov.:

AF XY:

0.276

AC XY:

20450

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.182

Gnomad4 AMR

AF:

0.246

Gnomad4 ASJ

AF:

0.274

Gnomad4 EAS

AF:

0.340

Gnomad4 SAS

AF:

0.371

Gnomad4 FIN

AF:

0.361

Gnomad4 NFE

AF:

0.308

Gnomad4 OTH

AF:

0.260

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 22, 2021	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	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

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

MutationTaster

Benign

0.096

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

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