rs886041310

chr19-4117539-T-Achr19-4117539-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate

The NM_030662.4(MAP2K2):c.183A>T(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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K61E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 16 ACMG points.

• PS1: Transcript NM_030662.4 (MAP2K2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 279998
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr19-4117541-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.183A>T	p.Lys61Asn	missense_variant	2/11	1	NM_030662.4	P1
MAP2K2	ENST00000394867.9	n.622A>T		non_coding_transcript_exon_variant	1/10	5
MAP2K2	ENST00000599345.1	n.380A>T		non_coding_transcript_exon_variant	2/7	5
MAP2K2	ENST00000687128.1	n.622A>T		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 06, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys61Asn variant in MAP2K2 has not been previously reported in individuals with Noonan sp ectrum disorders or in large population studies. However, another variant (p.Lys 61Glu) at the same codon was identified in two probands with clinical features o f Cardio-facio-cutaneous syndrome, and a third variant (p.Lys61Thr) at the same codon was reported to have occurred de novo in one proband with a RASopathy (Nar umi 2007, Nava 2007, Wong Ramsey 2014), suggesting that changes at this position may not be tolerated. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summar y, while there is some suspicion for a pathogenic role, the clinical significanc e of the p.Lys61Asn variant is uncertain. -

Noonan syndrome with multiple lentigines Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

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- -

Noonan syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

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- -

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	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D
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)		0.010		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;