rs267607230

chr19-4110576-G-Achr19-4110576-G-Cchr19-4110576-G-T

Variant summary

Our verdict is Pathogenic. Variant got 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 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 criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.87

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 id 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]. Clinvar id is 666272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.383C>T	p.Pro128Leu	missense_variant	3/11	ENST00000262948.10
MAP2K2	XM_006722799.3	c.383C>T	p.Pro128Leu	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.383C>T	p.Pro128Leu	missense_variant	3/11	1	NM_030662.4	P1
MAP2K2	ENST00000394867.9	n.822C>T		non_coding_transcript_exon_variant	2/10	5
MAP2K2	ENST00000599345.1	n.580C>T		non_coding_transcript_exon_variant	3/7	5
MAP2K2	ENST00000687128.1	n.822C>T		non_coding_transcript_exon_variant	2/7

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MAP2K2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

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

Pathogenic, no assertion criteria provided

clinical testing

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

Aug 12, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2023

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 (Yoshimi et al., 2020); A published functional study demonstrates a damaging effect, including increased activation of MAPK signaling and increased cell proliferation (Yoshimi et al., 2020); 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) -

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;.
MutationTaster	Benign	1.0	D;D
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

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: rs267607230; hg19: chr19-4110574; COSMIC: COSV53567689;