rs17851657
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137943/MONDO:0021060/004
Frequency
Genomes: 𝑓 0.14 ( 1972 hom., cov: 33)
Exomes 𝑓: 0.19 ( 27044 hom. )
Consequence
MAP2K2
NM_030662.4 splice_region, synonymous
NM_030662.4 splice_region, synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.278
Genes affected
MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BA1
?
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.453C>T | p.Asp151= | splice_region_variant, synonymous_variant | 4/11 | ENST00000262948.10 | |
MAP2K2 | XM_006722799.3 | c.453C>T | p.Asp151= | splice_region_variant, synonymous_variant | 4/9 | ||
MAP2K2 | XM_047439100.1 | c.-118C>T | splice_region_variant, 5_prime_UTR_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.453C>T | p.Asp151= | splice_region_variant, synonymous_variant | 4/11 | 1 | NM_030662.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.141 AC: 21512AN: 152112Hom.: 1967 Cov.: 33
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GnomAD3 exomes AF: 0.163 AC: 36340AN: 222968Hom.: 3477 AF XY: 0.170 AC XY: 20555AN XY: 120626
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GnomAD4 exome AF: 0.188 AC: 271555AN: 1443232Hom.: 27044 Cov.: 31 AF XY: 0.189 AC XY: 135803AN XY: 716686
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GnomAD4 genome ? AF: 0.141 AC: 21533AN: 152230Hom.: 1972 Cov.: 33 AF XY: 0.140 AC XY: 10386AN XY: 74422
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ClinVar
Significance: Benign
Submissions summary: Benign:11Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 29, 2008 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
RASopathy Benign:3
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | May 09, 2017 | The filtering allele frequency of the c.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) - |
Benign, no assertion criteria provided | clinical testing | Baylor Genetics | - | Variant classified using ACMG guidelines - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Cardiofaciocutaneous syndrome 4 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 21, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at