19-4117551-A-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Moderate
The ENST00000262948.10(MAP2K2):c.171T>A(p.Phe57Leu) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F57C) has been classified as Pathogenic.
Frequency
Consequence
ENST00000262948.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.171T>A | p.Phe57Leu | missense_variant | 2/11 | ENST00000262948.10 | NP_109587.1 | |
MAP2K2 | XM_006722799.3 | c.171T>A | p.Phe57Leu | missense_variant | 2/9 | XP_006722862.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.171T>A | p.Phe57Leu | missense_variant | 2/11 | 1 | NM_030662.4 | ENSP00000262948 | P1 | |
MAP2K2 | ENST00000394867.9 | n.610T>A | non_coding_transcript_exon_variant | 1/10 | 5 | |||||
MAP2K2 | ENST00000599345.1 | n.368T>A | non_coding_transcript_exon_variant | 2/7 | 5 | |||||
MAP2K2 | ENST00000687128.1 | n.610T>A | non_coding_transcript_exon_variant | 1/7 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2018 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe57 amino acid residue in MAP2K2. Other variant(s) that disrupt this residue have been observed in individuals with MAP2K2-related conditions (PMID: 18042262, 19156172, 16439621), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with cardio-facio-cutaneous (CFC) syndrome (PMID: 18456719) and was observed to be de novo in an individual with clinical features of CFC (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 57 of the MAP2K2 protein (p.Phe57Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at