12-40320043-G-C

Position:

chr12-40320043-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_198578.4(LRRK2):c.4883G>C(p.Arg1628Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000967 in 1,611,674 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1628H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00092 ( 3 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1B:5O:1

Conservation

PhyloP100: 9.23

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010469884).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00141 (214/152114) while in subpopulation EAS AF= 0.0244 (126/5174). AF 95% confidence interval is 0.0209. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.4883G>C	p.Arg1628Pro	missense_variant	34/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12 linkuse as main transcript	c.4883G>C	p.Arg1628Pro	missense_variant	34/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0243

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000574

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00187

AC:

469

AN:

250278

Hom.:

AF XY:

0.00182

AC XY:

247

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.000876

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0201

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000922

AC:

1345

AN:

1459560

Hom.:

Cov.:

AF XY:

0.000921

AC XY:

669

AN XY:

726076

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00838

Gnomad4 SAS exome

AF:

0.000361

Gnomad4 FIN exome

AF:

0.000824

Gnomad4 NFE exome

AF:

0.000758

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152114

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000939

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0244

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000574

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000335

Hom.:

Bravo

AF:

0.00126

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00175

AC:

212

Asia WGS

AF:

0.00578

AC:

AN:

3476

EpiCase

AF:

0.000328

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Pathogenic:1Uncertain:1Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, flagged submission	provider interpretation	Codex Genetics Limited	Feb 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jan 08, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	- -

Autosomal dominant Parkinson disease 8;C1861689:Klippel-Feil syndrome 1, autosomal dominant

Pathogenic:1

Pathogenic, flagged submission

provider interpretation

Codex Genetics Limited

Feb 28, 2019

- -

Early onset Alzheimer disease with behavioral disturbance

Pathogenic:1

Likely pathogenic, flagged submission

provider interpretation

Codex Genetics Limited

Feb 28, 2019

- -

Spinocerebellar atrophy

Pathogenic:1

Pathogenic, flagged submission

provider interpretation

Codex Genetics Limited

Feb 28, 2019

- -

Parkinson disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

East Asian population allele frequency is 1.844% (rs33949390, 413/19,932 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2021

This variant is associated with the following publications: (PMID: 27812003, 25511328, 27133195, 24997548, 29209554, 29029963, 30954774, 30917570, 24095219, 26311745, 26930193, 18412265, 25761573, 22575234, 18716801, 20018409, 19672984, 24488318, 21885347, 20571044, 20186690, 23421816, 19699188, 25243190, 20642453) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.0032

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.55

Sift

Benign

0.040

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.90

MVP

0.95

MPC

0.52

ClinPred

0.065

GERP RS

5.5

Varity_R

0.90

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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