chr12-40314059-C-T

Position:

chr12-40314059-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198578.4(LRRK2):c.4624C>T(p.Pro1542Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0315 in 1,612,210 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 145 hom., cov: 32)

Exomes 𝑓: 0.032 ( 1065 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.49

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028391778).

BP6

Variant 12-40314059-C-T is Benign according to our data. Variant chr12-40314059-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 39193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40314059-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0296 (4497/151954) while in subpopulation NFE AF= 0.035 (2380/67924). AF 95% confidence interval is 0.0339. There are 145 homozygotes in gnomad4. There are 2447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4497 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.4624C>T	p.Pro1542Ser	missense_variant	32/51	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.4624C>T	p.Pro1542Ser	missense_variant	32/51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0296

AC:

4497

AN:

151836

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00532

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0350

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0318

AC:

7966

AN:

250762

Hom.:

277

AF XY:

0.0318

AC XY:

4309

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00928

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0306

GnomAD4 exome

AF:

0.0317

AC:

46326

AN:

1460256

Hom.:

1065

Cov.:

AF XY:

0.0314

AC XY:

22843

AN XY:

726462

show subpopulations

Gnomad4 AFR exome

AF:

0.00356

Gnomad4 AMR exome

AF:

0.0226

Gnomad4 ASJ exome

AF:

0.0178

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00942

Gnomad4 FIN exome

AF:

0.120

Gnomad4 NFE exome

AF:

0.0322

Gnomad4 OTH exome

AF:

0.0294

GnomAD4 genome

AF:

0.0296

AC:

4497

AN:

151954

Hom.:

145

Cov.:

AF XY:

0.0329

AC XY:

2447

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00531

Gnomad4 AMR

AF:

0.0192

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00727

Gnomad4 FIN

AF:

0.138

Gnomad4 NFE

AF:

0.0350

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0288

Hom.:

109

Bravo

AF:

0.0188

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0329

AC:

283

ExAC

AF:

0.0300

AC:

3645

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0264

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

not provided, no classification provided	literature only	GeneReviews	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	This variant is associated with the following publications: (PMID: 32677286, 26503572) -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.16

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.49

MPC

0.42

ClinPred

0.028

GERP RS

5.8

Varity_R

0.11

gMVP

0.78

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