12-40293624-G-C

Position:

chr12-40293624-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_198578.4(LRRK2):c.2769G>C(p.Gln923His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,611,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 0.0930

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1672214).

BP6

Variant 12-40293624-G-C is Benign according to our data. Variant chr12-40293624-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39153.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4 linkuse as main transcript	c.2769G>C	p.Gln923His	missense_variant	21/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LRRK2	ENST00000298910.12 linkuse as main transcript	c.2769G>C	p.Gln923His	missense_variant	21/51	1	NM_198578.4	ENSP00000298910	P1
LRRK2	ENST00000680790.1 linkuse as main transcript	c.2514G>C	p.Gln838His	missense_variant	19/49			ENSP00000505335
LRRK2	ENST00000343742.6 linkuse as main transcript	c.2769G>C	p.Gln923His	missense_variant	21/27	5		ENSP00000341930
LRRK2	ENST00000679360.1 linkuse as main transcript	c.*1678G>C		3_prime_UTR_variant, NMD_transcript_variant	22/51			ENSP00000505368

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000199

AC:

AN:

250650

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000784

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1459646

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

105

AN XY:

726156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000785

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000145

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LRRK2: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2017	The Q923H variant in the LRRK2 gene has been reported previously in families with autosomal dominant Parkinson disease, however it was not found to segregate with disease in these families (Camargos et al., 2009; Jasinska-Myga et al., 2010). The Q923H variant has also been reported in individuals with sporadic Parkinson disease, however it is also seen at a similar frequency in control subjects (Jasinska-Myga et al., 2010; Ross et al., 2011). The Q923H variant is observed in 7/11236 (0.06%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). The Q923H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Q923H as a variant of uncertain significance. -

Autosomal dominant Parkinson disease 8

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.3

.;M

MutationTaster

Benign

0.89

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.27

Sift

Benign

0.047

D;D

Sift4G

Uncertain

0.045

D;T

Polyphen

0.99

D;D

Vest4

0.47

MutPred

0.35

Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);

MVP

0.79

MPC

0.38

ClinPred

0.092

GERP RS

-1.9

Varity_R

0.072

gMVP

0.16

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