15-66435070-C-T

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

Scores

9
7
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 0.490
Variant links:
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
MAP2K1NM_002755.4 linkc.124C>T p.Leu42Phe missense_variant Exon 2 of 11 ENST00000307102.10 NP_002746.1 Q02750-1A4QPA9
MAP2K1NM_001411065.1 linkc.58C>T p.Leu20Phe missense_variant Exon 2 of 10 NP_001397994.1
MAP2K1XM_011521783.4 linkc.58C>T p.Leu20Phe missense_variant Exon 2 of 11 XP_011520085.1 B4DFY5
MAP2K1XM_017022411.3 linkc.124C>T p.Leu42Phe missense_variant Exon 2 of 10 XP_016877900.1 Q02750-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K1ENST00000307102.10 linkc.124C>T p.Leu42Phe missense_variant Exon 2 of 11 1 NM_002755.4 ENSP00000302486.5 Q02750-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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 providedclinical testingPediatric Genetics Clinic, Sheba Medical CenterMay 13, 2021- -
Cardio-facio-cutaneous syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 21, 2014The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 14, 2023In 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 27, 2021Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D
Eigen
Benign
0.036
Eigen_PC
Benign
0.030
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.020
D
Polyphen
0.75
P
Vest4
0.88
MutPred
0.73
Loss of solvent accessibility (P = 0.0117);
MVP
0.98
MPC
1.4
ClinPred
0.94
D
GERP RS
3.2
Varity_R
0.67
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397516789; hg19: chr15-66727408; COSMIC: COSV61071728; API