NM_030662.4:c.376A>G

Variant names:

• chr19-4110583-T-C
• rs1057519806
• NM_030662.4:c.376A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_030662.4(MAP2K2):​c.376A>G​(p.Asn126Asp) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 19-4110583-T-C is Pathogenic according to our data. Variant chr19-4110583-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.376A>G	p.Asn126Asp	missense_variant	Exon 3 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.376A>G	p.Asn126Asp	missense_variant	Exon 3 of 9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.376A>G	p.Asn126Asp	missense_variant	Exon 3 of 11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.815A>G		non_coding_transcript_exon_variant	Exon 2 of 10	5
MAP2K2	ENST00000599345.1	n.573A>G		non_coding_transcript_exon_variant	Exon 3 of 7	5
MAP2K2	ENST00000687128.1	n.815A>G		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiofaciocutaneous syndrome 4 Pathogenic:1

Jun 11, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Aug 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with aspartic acid at codon 126 of the MAP2K2 protein (p.Asn126Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of MAP2K2-related conditions (PMID: 25487361; Invitae). ClinVar contains an entry for this variant (Variation ID: 376176). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.43	N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.081	T;T
Sift4G	Benign	0.23	T;T
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.34		Gain of phosphorylation at Y129 (P = 0.1415);.;
MVP		0.71
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.57

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

Other links and lift over

dbSNP: rs1057519806; hg19: chr19-4110581; COSMIC: COSV53566961;