12-40310461-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_198578.4(LRRK2):c.4348G>A(p.Val1450Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000645 in 1,612,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. V1450A) has been classified as Uncertain significance.
Frequency
Consequence
NM_198578.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRRK2 | NM_198578.4 | c.4348G>A | p.Val1450Ile | missense_variant | 31/51 | ENST00000298910.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRRK2 | ENST00000298910.12 | c.4348G>A | p.Val1450Ile | missense_variant | 31/51 | 1 | NM_198578.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000795 AC: 12AN: 150986Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251196Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135748
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461722Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44AN XY: 727168
GnomAD4 genome AF: 0.0000794 AC: 12AN: 151104Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 3AN XY: 73784
ClinVar
Submissions by phenotype
Autosomal dominant Parkinson disease 8 Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 39187). This missense change has been observed in individual(s) with clinical features of LRRK2-related conditions (PMID: 21885347, 23124679, 24565865, 32398759). This variant is present in population databases (rs111501952, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1450 of the LRRK2 protein (p.Val1450Ile). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at