chr12-40225152-G-T

Variant summary

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

The NM_198578.4(LRRK2):​c.21G>T​(p.Gln7His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,766 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 (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.364
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=0.09732166).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRK2NM_198578.4 linkuse as main transcriptc.21G>T p.Gln7His missense_variant 1/51 ENST00000298910.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRK2ENST00000298910.12 linkuse as main transcriptc.21G>T p.Gln7His missense_variant 1/511 NM_198578.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461766
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 11, 2023This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 7 of the LRRK2 protein (p.Gln7His). This variant has not been reported in the literature in individuals affected with LRRK2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.024
T;T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.73
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.097
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.4
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.071
Sift
Benign
0.034
D;D
Sift4G
Benign
0.16
T;D
Polyphen
0.45
.;P
Vest4
0.21
MutPred
0.14
Gain of glycosylation at S3 (P = 0.0665);Gain of glycosylation at S3 (P = 0.0665);
MVP
0.66
MPC
0.15
ClinPred
0.15
T
GERP RS
1.1
Varity_R
0.12
gMVP
0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-40618954; API