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-G
• chr19-4117552-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4_Moderate PM5 PM1 PS3_Supporting PM6 PP3 PM2_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

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.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.170T>G	p.Phe57Cys	missense_variant	Exon 2 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.170T>G	p.Phe57Cys	missense_variant	Exon 2 of 9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.170T>G	p.Phe57Cys	missense_variant	Exon 2 of 11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.609T>G		non_coding_transcript_exon_variant	Exon 1 of 10	5
MAP2K2	ENST00000599345.1	n.367T>G		non_coding_transcript_exon_variant	Exon 2 of 7	5
MAP2K2	ENST00000687128.1	n.609T>G		non_coding_transcript_exon_variant	Exon 1 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.00418 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Cardio-facio-cutaneous syndrome Other:2

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GenomeConnect - CFC International

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant reported as having been "documented to be causative for CFC syndrome" and reported on 05-11-2006 by lab or GTR ID Prevention Genetics. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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not provided Pathogenic:1

Jul 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate increased kinase activity and activation of downstream effectors (PMID: 18413255); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 16439621, 19156172, 22177953, 22753777, 25370473, 26399658, 29493581, 18413255) -

RASopathy Pathogenic:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Cardiofaciocutaneous syndrome 4 Pathogenic:1

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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
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

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