rs267607230

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-4110576-G-A
• chr19-4110576-G-C
• chr19-4110576-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_030662.4(MAP2K2):​c.383C>T​(p.Pro128Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P128Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_030662.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-4110576-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8275.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 19-4110576-G-A is Pathogenic according to our data. Variant chr19-4110576-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 666272.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.383C>T	p.Pro128Leu	missense_variant	Exon 3 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.383C>T	p.Pro128Leu	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>T	p.Pro128Leu	missense_variant	Exon 3 of 11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.822C>T		non_coding_transcript_exon_variant	Exon 2 of 10	5
MAP2K2	ENST00000599345.1	n.580C>T		non_coding_transcript_exon_variant	Exon 3 of 7	5
MAP2K2	ENST00000687128.1	n.822C>T		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MAP2K2-related disorder Pathogenic:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MAP2K2 c.383C>T variant is predicted to result in the amino acid substitution p.Pro128Leu. This variant was reported as a somatic variant in an individual with TAFRO, which is a clinical subtype of idiopathic multicentric Castleman disease (iMCD) syndrome (iMCD-TARFO) (Patient 1, Yoshimi et al 2020. PubMed ID: 32051554). Functional studies of this variant showed it lead to hyperactivated MAP kinase signaling, conferred IL-3 hypersensitivity, and sensitized the cells to MEK inhibitors (Yoshimi et al. 2020. PubMed ID: 32051554). At PreventionGenetics, this variant has been reported de novo in a fetus with non-immune hydrops fetalis (Internal Data). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Castleman-Kojima disease Pathogenic:1

Aug 12, 2019

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 28, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as a somatic variant via lymph node biopsy testing in a patient with Castleman disease in published literature, though this variant was absent in bone marrow and the patient did not exhibit features of MAP2K2-related RASopathy (PMID: 32051554); A published functional study demonstrates a damaging effect, including increased activation of MAPK signaling and increased cell proliferation (PMID: 32051554); 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: 32051554, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581) -

Cardiofaciocutaneous syndrome 4 Pathogenic:1

Nov 12, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.89		Loss of catalytic residue at N126 (P = 0.1104);.;
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.70
Mutation Taster		=2/98	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; COSMIC: COSV53567689;