19-4110558-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_030662.4(MAP2K2):​c.401A>C​(p.Tyr134Ser) 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. 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

14
4
1

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 Likely_pathogenic. Variant got 8 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].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K2NM_030662.4 linkc.401A>C p.Tyr134Ser missense_variant Exon 3 of 11 ENST00000262948.10 NP_109587.1 P36507
MAP2K2XM_006722799.3 linkc.401A>C p.Tyr134Ser 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>C p.Tyr134Ser missense_variant Exon 3 of 11 1 NM_030662.4 ENSP00000262948.4 P36507
MAP2K2ENST00000394867.9 linkn.840A>C non_coding_transcript_exon_variant Exon 2 of 10 5
MAP2K2ENST00000599345.1 linkn.598A>C non_coding_transcript_exon_variant Exon 3 of 7 5
MAP2K2ENST00000687128.1 linkn.840A>C 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.45
T;T
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.9
M;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-7.6
D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.91
MutPred
0.87
Gain of glycosylation at Y134 (P = 0.021);.;
MVP
0.98
MPC
1.6
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.79

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