dbSNP rs34594498: LRRK2:p.Ala419Glu (chr12-40252984-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_198578.4(LRRK2):c.1256C>A(p.Ala419Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A419V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.15

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.1256C>A	p.Ala419Glu	missense_variant	Exon 11 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.1256C>A	p.Ala419Glu	missense_variant	Exon 11 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460464

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39578

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110982

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

T;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.40

MutationAssessor

Benign

2.0

.;M

PhyloP100

4.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.26

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.96

D;D

Vest4

0.75

MutPred

0.51

Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);

MVP

0.80

MPC

0.49

ClinPred

0.95

GERP RS

5.1

Varity_R

0.39

gMVP

0.57

Mutation Taster

=71/29

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over