12-40304000-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_198578.4(LRRK2):c.3643G>A(p.Ala1215Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1215E) has been classified as Uncertain significance.
Frequency
Consequence
NM_198578.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRRK2 | NM_198578.4 | c.3643G>A | p.Ala1215Thr | missense_variant | 27/51 | ENST00000298910.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRRK2 | ENST00000298910.12 | c.3643G>A | p.Ala1215Thr | missense_variant | 27/51 | 1 | NM_198578.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 151976Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000996 AC: 25AN: 251054Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135676
GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461518Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55AN XY: 727052
GnomAD4 genome AF: 0.000125 AC: 19AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74332
ClinVar
Submissions by phenotype
Autosomal dominant Parkinson disease 8 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 08, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 26, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1215 of the LRRK2 protein (p.Ala1215Thr). This variant is present in population databases (rs143710836, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 27393345). ClinVar contains an entry for this variant (Variation ID: 444287). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRRK2 protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at