19-4110558-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3PM1PM2PP2PP3

This summary comes from the ClinGen Evidence Repository: The c.401A>G (p.Tyr134Cys) variant in MAP2K2 has been identified in one patient with clinical features of a RASopathy (PMID 18413255). In vitro functional studies provide some evidence that the p.Tyr134Cys variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr134Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM2, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180890/MONDO:0015280/004

Frequency

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

Consequence

MAP2K2
NM_030662.4 missense

Scores

13
5
1

Clinical Significance

Pathogenic reviewed by expert panel P:5O:1

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 Pathogenic. Variant got 10 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K2NM_030662.4 linkc.401A>G p.Tyr134Cys missense_variant Exon 3 of 11 ENST00000262948.10 NP_109587.1 P36507
MAP2K2XM_006722799.3 linkc.401A>G p.Tyr134Cys 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>G p.Tyr134Cys missense_variant Exon 3 of 11 1 NM_030662.4 ENSP00000262948.4 P36507
MAP2K2ENST00000394867.9 linkn.840A>G non_coding_transcript_exon_variant Exon 2 of 10 5
MAP2K2ENST00000599345.1 linkn.598A>G non_coding_transcript_exon_variant Exon 3 of 7 5
MAP2K2ENST00000687128.1 linkn.840A>G non_coding_transcript_exon_variant Exon 2 of 7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461718
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727154
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:1Other:1
May 09, 2017
ClinGen RASopathy Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.401A>G (p.Tyr134Cys) variant in MAP2K2 has been identified in one patient with clinical features of a RASopathy (PMID 18413255). In vitro functional studies provide some evidence that the p.Tyr134Cys variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr134Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM2, PM1, PP2, PP3. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
Feb 15, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Noonan syndrome 1 Pathogenic:1
-
Molecular Genetics, Centre for Human Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:1
Jul 22, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect in which the variant causes increased kinase activity and activation of downstream effectors (MEK and ERK), indicating a gain of function (Rodriguez-Viciana et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 29752777, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 18042262, 18413255) -

RASopathy Pathogenic:1
Oct 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the MAP2K2 protein (p.Tyr134Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cardio-facio-cutaneous syndrome (PMID: 18039235, 18413255, 23885229). This variant is also known as MEK2 Y134C. ClinVar contains an entry for this variant (Variation ID: 177868). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MAP2K2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MAP2K2 function (PMID: 17981815, 18413255, 19376813). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Pathogenic
0.93
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
0.96
MutPred
0.94
Loss of sheet (P = 0.0817);.;
MVP
0.98
MPC
1.5
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727504370; hg19: chr19-4110556; COSMIC: COSV53564551; API