chr19-4110576-G-T

Variant names:

• chr19-4110576-G-T
• rs267607230
• NM_030662.4:c.383C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PS4_Supporting PM2_Supporting PM1 PS3_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.383C>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by glutamine at amino acid 128 (p.Pro128Gln). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928 (PP3). This variant is located in a functional domain supporting pathogenicity (PM1). This variant has been reported to segregate with clinical features of a RASopathy in at least 7 family members of the proband (PS4_Supporting, PP1_Strong; 20358587). ERK phosphorylation assay showed that this variant led to increased ERK phosphorylation compared to wild-type (PS3_P; PMID 20358587). 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: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA279962/MONDO:0015280/048

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 9.87
• Publications: 21 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: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 4

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 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.
• PP1: 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.383C>A	p.Pro128Gln	missense_variant	Exon 3 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.383C>A	p.Pro128Gln	missense_variant	Exon 3 of 9		NP_001427617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.383C>A	p.Pro128Gln	missense_variant	Exon 3 of 11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.822C>A		non_coding_transcript_exon_variant	Exon 2 of 10	5
MAP2K2	ENST00000599345.1	n.580C>A		non_coding_transcript_exon_variant	Exon 3 of 7	5
MAP2K2	ENST00000687128.1	n.822C>A		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00449 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

May 27, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro128Gln (CCG>CAG): c.383 C>A in exon 3 of the MAP2K2 gene (NM_030662.3). The P128Q missense mutation in the MAP2K2 gene has been reported previously in association with cardio-facio-cutaneous (CFC) syndrome (Rauen et al., 2009). Additionally, another mutation at the same codon (P128R) has been reported in association with CFC syndrome (Narumi et al., 2007). The variant is found in NOONAN panel(s).

RASopathy Pathogenic:1

Sep 17, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.383C>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by glutamine at amino acid 128 (p.Pro128Gln). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928 (PP3). This variant is located in a functional domain supporting pathogenicity (PM1). This variant has been reported to segregate with clinical features of a RASopathy in at least 7 family members of the proband (PS4_Supporting, PP1_Strong; 20358587). ERK phosphorylation assay showed that this variant led to increased ERK phosphorylation compared to wild-type (PS3_P; PMID 20358587). 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: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024)

Cardiofaciocutaneous syndrome 4 Pathogenic:1

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Cardio-facio-cutaneous syndrome Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D;D
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.85
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.66
Mutation Taster		=1/99	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: rs267607230; hg19: chr19-4110574;