19-4117539-T-G

Position:

• chr19-4117539-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_030662.4(MAP2K2):​c.183A>C​(p.Lys61Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.396

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 19-4117539-T-G is Pathogenic according to our data. Variant chr19-4117539-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.183A>C	p.Lys61Asn	missense_variant	2/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.183A>C	p.Lys61Asn	missense_variant	2/9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.183A>C	p.Lys61Asn	missense_variant	2/11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.622A>C		non_coding_transcript_exon_variant	1/10	5
MAP2K2	ENST00000599345.1	n.380A>C		non_coding_transcript_exon_variant	2/7	5
MAP2K2	ENST00000687128.1	n.622A>C		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2022

Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 32901917, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581) -

Cardiofaciocutaneous syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 02, 2021

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000279998.2, PS1_P). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Lys61Glu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040769.5, PMID: 25326637, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.653, 3Cnet: 0.951, PP3). Patient's phenotype is considered compatible with Cardiofaciocutaneous syndrome 4 (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys61 amino acid residue in MAP2K2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17366577, 24719372, 25326637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K2 protein function. ClinVar contains an entry for this variant (Variation ID: 279998). This missense change has been observed in individual(s) with MAP2K2-related conditions (PMID: 32901917). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 61 of the MAP2K2 protein (p.Lys61Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.48		Loss of ubiquitination at K61 (P = 0.0092);
MVP		0.92
MPC		1.4
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.95
gMVP		0.80

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: rs886041310; hg19: chr19-4117537;