chr19-4090612-G-A

Variant names:

• chr19-4090612-G-A
• rs730880516
• NM_030662.4:c.1189C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_030662.4(MAP2K2):​c.1189C>T​(p.Arg397Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,399,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R397H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.58
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3838683).
• BP6: Variant 19-4090612-G-A is Benign according to our data. Variant chr19-4090612-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180910.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.1189C>T	p.Arg397Cys	missense_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.910C>T	p.Arg304Cys	missense_variant	Exon 9 of 9		NP_001427617.1
MAP2K2	NM_001440689.1	c.619C>T	p.Arg207Cys	missense_variant	Exon 9 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.1189C>T	p.Arg397Cys	missense_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000190 AC: 3 AN: 157742 AF XY: 0.0000359

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000872

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1399210 Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9 AN XY: 690428

African (AFR) AF: 0.00 AC: 0 AN: 31678

American (AMR) AF: 0.0000279 AC: 1 AN: 35826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.0000557 AC: 2 AN: 35878

South Asian (SAS) AF: 0.00 AC: 0 AN: 79344

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00000741 AC: 8 AN: 1079550

Other (OTH) AF: 0.00 AC: 0 AN: 57990

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAP2K2: BP4 -

Jun 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with a RASopathy who was also heterozygous for a variant in the KAT6B gene in the reported literature (PMID: 35418823); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Located in the Versatile Docking Domain (PMID: 29493581); This variant is associated with the following publications: (PMID: 38737102, 29493581, 35418823) -

RASopathy Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 397 of the MAP2K2 protein (p.Arg397Cys). This variant is present in population databases (rs730880516, gnomAD 0.01%). This missense change has been observed in individual(s) with RASopathy (PMID: 35418823). ClinVar contains an entry for this variant (Variation ID: 180910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAP2K2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		9.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.99	D;.
Vest4		0.49
MutPred		0.31		Loss of solvent accessibility (P = 0.0146);.;
MVP		0.74
MPC		1.1
ClinPred		0.82	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.76
Mutation Taster		=52/48	polymorphism

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: rs730880516; hg19: chr19-4090610; COSMIC: COSV53570312; COSMIC: COSV53570312;