rs730880523

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030662.4(MAP2K2):​c.856G>T​(p.Gly286Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,256 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 missense

Scores

2
10
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.04
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAP2K2NM_030662.4 linkuse as main transcriptc.856G>T p.Gly286Trp missense_variant 7/11 ENST00000262948.10 NP_109587.1 P36507
MAP2K2XM_047439100.1 linkuse as main transcriptc.286G>T p.Gly96Trp missense_variant 5/9 XP_047295056.1
MAP2K2XM_006722799.3 linkuse as main transcriptc.705+1755G>T intron_variant XP_006722862.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAP2K2ENST00000262948.10 linkuse as main transcriptc.856G>T p.Gly286Trp missense_variant 7/111 NM_030662.4 ENSP00000262948.4 P36507

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1453256
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
722384
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T;T
Eigen
Benign
-0.095
Eigen_PC
Benign
-0.17
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.66
D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.44
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.012
D;D
Polyphen
0.83
P;.
Vest4
0.57
MutPred
0.41
Loss of disorder (P = 0.0643);.;
MVP
0.87
MPC
1.2
ClinPred
0.89
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.080
gMVP
0.71

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: chr19-4099262; COSMIC: COSV53570018; COSMIC: COSV53570018; API