rs727504382

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030662.4(MAP2K2):​c.619G>T​(p.Glu207*) variant causes a stop gained 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. Synonymous variant affecting the same amino acid position (i.e. E207E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MAP2K2
NM_030662.4 stop_gained

Scores

5
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.86

Publications

0 publications found
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]
MAP2K2 Gene-Disease associations (from GenCC):
  • cardiofaciocutaneous syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • cardiofaciocutaneous syndrome 4
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • neurofibromatosis-Noonan syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Noonan syndrome
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K2NM_030662.4 linkc.619G>T p.Glu207* stop_gained Exon 6 of 11 ENST00000262948.10 NP_109587.1 P36507
MAP2K2NM_001440688.1 linkc.619G>T p.Glu207* stop_gained Exon 6 of 9 NP_001427617.1
MAP2K2NM_001440689.1 linkc.49G>T p.Glu17* stop_gained Exon 4 of 9 NP_001427618.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K2ENST00000262948.10 linkc.619G>T p.Glu207* stop_gained Exon 6 of 11 1 NM_030662.4 ENSP00000262948.4 P36507

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1454416
Hom.:
0
Cov.:
53
AF XY:
0.00
AC XY:
0
AN XY:
722732
African (AFR)
AF:
0.00
AC:
0
AN:
33252
American (AMR)
AF:
0.00
AC:
0
AN:
43812
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25964
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39228
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84644
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52868
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5728
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1108824
Other (OTH)
AF:
0.00
AC:
0
AN:
60096
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
49
DANN
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.98
D
PhyloP100
7.9
Vest4
0.97
GERP RS
4.2
PromoterAI
-0.054
Neutral
Mutation Taster
=4/196
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs727504382; hg19: chr19-4101103; API