19-4110564-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_030662.4(MAP2K2):c.395G>A(p.Gly132Asp) 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. G132V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_030662.4 missense
Scores
Clinical Significance
Conservation
Publications
- cardiofaciocutaneous syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- cardiofaciocutaneous syndrome 4Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Noonan syndromeInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.395G>A | p.Gly132Asp | missense_variant | Exon 3 of 11 | 1 | NM_030662.4 | ENSP00000262948.4 | ||
MAP2K2 | ENST00000394867.9 | n.834G>A | non_coding_transcript_exon_variant | Exon 2 of 10 | 5 | |||||
MAP2K2 | ENST00000599345.1 | n.592G>A | non_coding_transcript_exon_variant | Exon 3 of 7 | 5 | |||||
MAP2K2 | ENST00000687128.1 | n.834G>A | non_coding_transcript_exon_variant | Exon 2 of 7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardiofaciocutaneous syndrome 4 Pathogenic:2
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not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 31040167, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 34184824, 21178588, 36964972) -
Cardiovascular phenotype Pathogenic:1
The c.395G>A (p.G132D) alteration is located in exon 3 (coding exon 3) of the MAP2K2 gene. This alteration results from a G to A substitution at nucleotide position 395, causing the glycine (G) at amino acid position 132 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individuals with developmental delay, learning difficulties, pulmonary stenosis, short stature, absent eyebrows, hyperelastic skin, palmoplantar hyperkeratosis, and/or other clinical features consistent with MAP2K2-related RASopathy (Linden, 2011; Uluda Alkaya, 2021; Gorukmez, 2023; NCBI ClinVar). Another variant at the same codon, c.395G>T (p.G132V), and another variant at the similar codon in the paralog MAP2K1, c.383G>T (p.G128V), have been identified in individual(s) with features consistent with RASopathies (Narumi, 2007; Schulz, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
RASopathy Pathogenic:1
Variant classified using ACMG guidelines -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at