rs1057519806
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_030662.4(MAP2K2):c.376A>G(p.Asn126Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N126H) has been classified as Uncertain significance.
Frequency
Consequence
NM_030662.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.376A>G | p.Asn126Asp | missense_variant | 3/11 | ENST00000262948.10 | |
MAP2K2 | XM_006722799.3 | c.376A>G | p.Asn126Asp | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.376A>G | p.Asn126Asp | missense_variant | 3/11 | 1 | NM_030662.4 | P1 | |
MAP2K2 | ENST00000394867.9 | n.815A>G | non_coding_transcript_exon_variant | 2/10 | 5 | ||||
MAP2K2 | ENST00000599345.1 | n.573A>G | non_coding_transcript_exon_variant | 3/7 | 5 | ||||
MAP2K2 | ENST00000687128.1 | n.815A>G | non_coding_transcript_exon_variant | 2/7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardio-facio-cutaneous syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Melanoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Dec 26, 2014 | - - |
RASopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K2 protein function. ClinVar contains an entry for this variant (Variation ID: 376176). This missense change has been observed in individuals with clinical features of MAP2K2-related conditions (PMID: 25487361; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 126 of the MAP2K2 protein (p.Asn126Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. - |
Cardiofaciocutaneous syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 11, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at