rs761150136
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_002755.4(MAP2K1):āc.11A>Gā(p.Lys4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_002755.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000116 AC: 2AN: 172566Hom.: 0 AF XY: 0.0000218 AC XY: 2AN XY: 91804
GnomAD4 exome AF: 0.00000283 AC: 4AN: 1411230Hom.: 0 Cov.: 32 AF XY: 0.00000574 AC XY: 4AN XY: 697246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Variant summary: The c.11A>G (p.Lys4Arg) in MAP2K1 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain and no functional studies implying the impact of this varian ton protein function have been published at the time of evaluation. The variant is absent from the control population dataset of ExAC (0/ 21980 chrs tested). Small numbers of sample in ExAC database indicate a low coverage site, therefore this data should be reviewed with caution. The variant is present in control population of gnomAD at a frequency of 0.00001208 (2/ 165522 chrs tested), which exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.0000025). The presence of the variant in presumably unaffected individual in gnomAD suggests a benign outcome, as mutations in MAP2K1 are extremely rare in hematologic malignancy (COSMIC). The variant has not, to our knowledge, been reported in affected individuals via published reports or by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more evidence becomes available. -
The MAP2K1 c.11A>G; p.Lys4Arg variant (rs761150136), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 496174). This variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.371). Due to limited information, the clinical significance of this variant is uncertain at this time. -
RASopathy Uncertain:1
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 4 of the MAP2K1 protein (p.Lys4Arg). This variant is present in population databases (rs761150136, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MAP2K1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496174). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAP2K1 protein function with a negative predictive value of 95%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at