19-4110639-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_030662.4(MAP2K2):​c.320T>A​(p.Ile107Asn) 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MAP2K2
NM_030662.4 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.20
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAP2K2NM_030662.4 linkuse as main transcriptc.320T>A p.Ile107Asn missense_variant 3/11 ENST00000262948.10 NP_109587.1
MAP2K2XM_006722799.3 linkuse as main transcriptc.320T>A p.Ile107Asn missense_variant 3/9 XP_006722862.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAP2K2ENST00000262948.10 linkuse as main transcriptc.320T>A p.Ile107Asn missense_variant 3/111 NM_030662.4 ENSP00000262948 P1
MAP2K2ENST00000394867.9 linkuse as main transcriptn.759T>A non_coding_transcript_exon_variant 2/105
MAP2K2ENST00000599345.1 linkuse as main transcriptn.517T>A non_coding_transcript_exon_variant 3/75
MAP2K2ENST00000687128.1 linkuse as main transcriptn.759T>A non_coding_transcript_exon_variant 2/7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 28, 2016The p.Ile107Asn variant in MAP2k2 has not been previously reported in individual s with RASopathies or in large population studies. Computational prediction tool s and conservation analysis suggest that the p.Ile107Asn variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, the clinical significance of the p.Ile107Asn variant is uncert ain. -
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 22, 2019This sequence change replaces isoleucine with asparagine at codon 107 of the MAP2K2 protein (p.Ile107Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant has not been reported in the literature in individuals with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 40790. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T;T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Benign
1.1
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.058
T;T
Polyphen
0.79
P;.
Vest4
0.76
MutPred
0.47
Gain of relative solvent accessibility (P = 0.0166);.;
MVP
0.94
MPC
0.97
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.92
gMVP
0.78

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: rs1555698037; hg19: chr19-4110637; API