chr12-40225160-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198578.4(LRRK2):ā€‹c.29A>Cā€‹(p.Glu10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E10K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15307963).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRK2NM_198578.4 linkuse as main transcriptc.29A>C p.Glu10Ala missense_variant 1/51 ENST00000298910.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRK2ENST00000298910.12 linkuse as main transcriptc.29A>C p.Glu10Ala missense_variant 1/511 NM_198578.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000798
AC:
2
AN:
250782
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135760
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461812
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2021The p.E10A variant (also known as c.29A>C), located in coding exon 1 of the LRRK2 gene, results from an A to C substitution at nucleotide position 29. The glutamic acid at codon 10 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.032
T;T
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.033
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.055
Sift
Uncertain
0.014
D;D
Sift4G
Benign
0.13
T;D
Polyphen
0.30
.;B
Vest4
0.20
MutPred
0.16
Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);
MVP
0.76
MPC
0.11
ClinPred
0.53
D
GERP RS
3.9
Varity_R
0.10
gMVP
0.23

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.

Other links and lift over

dbSNP: rs759670012; hg19: chr12-40618962; API