19-4110568-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_030662.4(MAP2K2):c.391G>A(p.Val131Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V131L) has been classified as Uncertain significance.
Frequency
Consequence
NM_030662.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.391G>A | p.Val131Met | missense_variant | 3/11 | ENST00000262948.10 | |
MAP2K2 | XM_006722799.3 | c.391G>A | p.Val131Met | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.391G>A | p.Val131Met | missense_variant | 3/11 | 1 | NM_030662.4 | P1 | |
MAP2K2 | ENST00000394867.9 | n.830G>A | non_coding_transcript_exon_variant | 2/10 | 5 | ||||
MAP2K2 | ENST00000599345.1 | n.588G>A | non_coding_transcript_exon_variant | 3/7 | 5 | ||||
MAP2K2 | ENST00000687128.1 | n.830G>A | non_coding_transcript_exon_variant | 2/7 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727140
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 04, 2012 | The Val131Met variant in MEK2 has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Val 131Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully as sess the clinical significance of the Val131Met variant. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 131 of the MAP2K2 protein (p.Val131Met). This variant is present in population databases (rs397517413, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of MAP2K2-related conditions (PMID: 26918529). ClinVar contains an entry for this variant (Variation ID: 46234). 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 MAP2K2 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at