rs11539506
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_030662.4(MAP2K2):c.846C>T(p.Pro282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,605,774 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0033 ( 16 hom. )
Consequence
MAP2K2
NM_030662.4 synonymous
NM_030662.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.581
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
?
Variant 19-4099274-G-A is Benign according to our data. Variant chr19-4099274-G-A is described in ClinVar as [Benign]. Clinvar id is 40827.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-4099274-G-A is described in Lovd as [Benign]. Variant chr19-4099274-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.581 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00279 (425/152282) while in subpopulation AMR AF= 0.00477 (73/15288). AF 95% confidence interval is 0.00389. There are 1 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd at 425 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.846C>T | p.Pro282= | synonymous_variant | 7/11 | ENST00000262948.10 | |
MAP2K2 | XM_047439100.1 | c.276C>T | p.Pro92= | synonymous_variant | 5/9 | ||
MAP2K2 | XM_006722799.3 | c.705+1745C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.846C>T | p.Pro282= | synonymous_variant | 7/11 | 1 | NM_030662.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00279 AC: 425AN: 152166Hom.: 1 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
425
AN:
152166
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00274 AC: 634AN: 231664Hom.: 1 AF XY: 0.00293 AC XY: 370AN XY: 126300
GnomAD3 exomes
AF:
AC:
634
AN:
231664
Hom.:
AF XY:
AC XY:
370
AN XY:
126300
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00335 AC: 4862AN: 1453492Hom.: 16 Cov.: 33 AF XY: 0.00328 AC XY: 2373AN XY: 722512
GnomAD4 exome
AF:
AC:
4862
AN:
1453492
Hom.:
Cov.:
33
AF XY:
AC XY:
2373
AN XY:
722512
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00279 AC: 425AN: 152282Hom.: 1 Cov.: 33 AF XY: 0.00278 AC XY: 207AN XY: 74470
GnomAD4 genome
?
AF:
AC:
425
AN:
152282
Hom.:
Cov.:
33
AF XY:
AC XY:
207
AN XY:
74470
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Benign
Submissions summary: Benign:11
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2010 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | MAP2K2: BP4, BP7, BS1 - |
RASopathy Benign:2
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | May 09, 2017 | The filtering allele frequency of the c.846C>T (p.Pro282=) variant in the MAP2K2 gene is 0.515% (46/6886) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 13, 2021 | - - |
Cardiofaciocutaneous syndrome 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at