rs886041310

Variant names:

• chr19-4117539-T-A
• rs886041310
• NM_030662.4:c.183A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-4117539-T-A
• chr19-4117539-T-C
• chr19-4117539-T-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate PP5

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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 0.396
• Publications: 5 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 17 ACMG points.

• PS1: Transcript NM_030662.4 (MAP2K2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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
• PP5: Variant 19-4117539-T-A is Pathogenic according to our data. Variant chr19-4117539-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505022.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.183A>T	p.Lys61Asn	missense_variant	Exon 2 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.183A>T	p.Lys61Asn	missense_variant	Exon 2 of 9		NP_001427617.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

May 15, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 34184824) -

not specified Uncertain:1

May 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome 1 Uncertain:1

-

Molecular Genetics, Centre for Human Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
PhyloP100		0.40
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
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs886041310; hg19: chr19-4117537;