15-66435070-C-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_002755.4(MAP2K1):c.124C>T(p.Leu42Phe) 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
MAP2K1
NM_002755.4 missense
NM_002755.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 0.490
Genes affected
MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the MAP2K1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 3.1085 (above the threshold of 3.09). Trascript score misZ: 3.7499 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 3, Costello syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.889
PP5
Variant 15-66435070-C-T is Pathogenic according to our data. Variant chr15-66435070-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44587.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAP2K1 | NM_002755.4 | c.124C>T | p.Leu42Phe | missense_variant | Exon 2 of 11 | ENST00000307102.10 | NP_002746.1 | |
MAP2K1 | NM_001411065.1 | c.58C>T | p.Leu20Phe | missense_variant | Exon 2 of 10 | NP_001397994.1 | ||
MAP2K1 | XM_011521783.4 | c.58C>T | p.Leu20Phe | missense_variant | Exon 2 of 11 | XP_011520085.1 | ||
MAP2K1 | XM_017022411.3 | c.124C>T | p.Leu42Phe | missense_variant | Exon 2 of 10 | XP_016877900.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiofaciocutaneous syndrome 3 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Pediatric Genetics Clinic, Sheba Medical Center | May 13, 2021 | - - |
Cardio-facio-cutaneous syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 21, 2014 | The p.Leu42Phe variant in MAP2K1 has been previously identified in two individua ls with clinical features of Cardio-facio-cutaneous syndrome (Dentici 2009, LMM unpublished data) and was identified to occur de novo in one individual (Dentici 2009). It was absent from large population studies. Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein. In summary, the p.Leu42Phe variant is likely pathogenic, th ough additional studies are required to fully establish its clinical significanc e. - |
RASopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2023 | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MAP2K1 function (PMID: 28049852, 29753091). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 44587). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome and/or clinical features of MAP2K1-related conditions (PMID: 19156172, 29907801, 30141192; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 42 of the MAP2K1 protein (p.Leu42Phe). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2021 | Variant summary: MAP2K1 c.124C>T (p.Leu42Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD). c.124C>T has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Dentici_2009, Alfieri_2012, Bessis_2019, Leoni_2020). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Jindal_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of solvent accessibility (P = 0.0117);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at