rs727504370

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_030662.4(MAP2K2):​c.401A>T​(p.Tyr134Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y134H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MAP2K2
NM_030662.4 missense

Scores

4
9
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.83
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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-4110559-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K2NM_030662.4 linkc.401A>T p.Tyr134Phe missense_variant Exon 3 of 11 ENST00000262948.10 NP_109587.1 P36507
MAP2K2XM_006722799.3 linkc.401A>T p.Tyr134Phe missense_variant Exon 3 of 9 XP_006722862.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K2ENST00000262948.10 linkc.401A>T p.Tyr134Phe missense_variant Exon 3 of 11 1 NM_030662.4 ENSP00000262948.4 P36507
MAP2K2ENST00000394867.9 linkn.840A>T non_coding_transcript_exon_variant Exon 2 of 10 5
MAP2K2ENST00000599345.1 linkn.598A>T non_coding_transcript_exon_variant Exon 3 of 7 5
MAP2K2ENST00000687128.1 linkn.840A>T non_coding_transcript_exon_variant Exon 2 of 7

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T;T
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.74
D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
1.6
L;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-2.9
D;D
REVEL
Pathogenic
0.70
Sift
Benign
0.12
T;T
Sift4G
Benign
0.099
T;T
Polyphen
0.24
B;.
Vest4
0.69
MutPred
0.80
Loss of sheet (P = 0.0817);.;
MVP
0.82
MPC
1.0
ClinPred
0.95
D
GERP RS
5.3
Varity_R
0.81
gMVP
0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4110556; API