rs121434497

Variant names:

• chr19-4117552-A-C
• rs121434497
• NM_030662.4:c.170T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-4117552-A-C
• chr19-4117552-A-T
• chr19-4117552-A-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PM2_Supporting PM6 PS4_Moderate PM5 PM1 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.170T>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of phenylalanine by cysteine at amino acid 57 (p.Phe57Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.959, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 47-65). Furthermore, other pathogenic missense variants has been previously identified at this codon of MAP2K2 (Phe57Val, Phe57Ile, Phe57Leu) and in nearby residues in association with CFC syndrome, which may indicate that this residue is critical to the function of the protein (PM5). This variant has been identified in at least 4 patients with RASopathy, of which 1 was an unconfirmed de novo occurrence (PS4_Moderate, PM6; GenomeConnect, ClinVar: SCV002047662.1; PMID:16439621, 18039235, 21062266). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID:16439621, 17981815). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM5, PM6, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA279958/MONDO:0021060/048

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:2
• Conservation: PhyloP100: 9.11
• Publications: 22 publications found

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: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030662.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	NM_030662.4	MANE Select	c.170T>G	p.Phe57Cys	missense	Exon 2 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.170T>G	p.Phe57Cys	missense	Exon 2 of 9	NP_001427617.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.170T>G	p.Phe57Cys	missense	Exon 2 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.170T>G	p.Phe57Cys	missense	Exon 2 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.170T>G	p.Phe57Cys	missense	Exon 2 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000106 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiofaciocutaneous syndrome 4 (1)
1	-	-	not provided (1)
1	-	-	RASopathy (1)
-	-	-	Cardio-facio-cutaneous syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.81		Gain of catalytic residue at L58 (P = 0.0195)
MVP		0.95
MPC		1.6
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.75
gMVP		0.79
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434497; hg19: chr19-4117550; COSMIC: COSV53562150;