19-4101105-C-T

Variant names:

• chr19-4101105-C-T
• rs727504382
• NM_030662.4:c.619G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2 PM2 PM6 PS4 PS2

This summary comes from the ClinGen Evidence Repository: The c.619G>A (p.Glu207Lys) variant in MAP2K2 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in 6 individuals with clinical features of a RASopathy (PS4; SCV000204213.4, SCV000207959.10, SCV000815593.1, Otto von Guericke University Magdeburg internal data). One of these cases was a confirmed de novo occurrence and another was an unconfirmed de novo occurrence (PS2; PM6; SCV000815593.1, Otto von Guericke University Magdeburg internal data). Additionally, the c.619G>A (p.Glu207Lys) is located in MAP2K2, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PS2, PM6, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180944/MONDO:0015280/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 O:1
• Conservation: PhyloP100: 7.86
• Publications: 16 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 13 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030662.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	NM_030662.4	MANE Select	c.619G>A	p.Glu207Lys	missense	Exon 6 of 11	NP_109587.1
	MAP2K2	NM_001440688.1		c.619G>A	p.Glu207Lys	missense	Exon 6 of 9	NP_001427617.1
	MAP2K2	NM_001440689.1		c.49G>A	p.Glu17Lys	missense	Exon 4 of 9	NP_001427618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.619G>A	p.Glu207Lys	missense	Exon 6 of 11	ENSP00000262948.4
	MAP2K2	ENST00000394867.9	TSL:5	n.1058G>A		non_coding_transcript_exon	Exon 5 of 10
	MAP2K2	ENST00000593364.5	TSL:5	n.566G>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000107 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Cardio-facio-cutaneous syndrome (2)
1	-	-	Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome (1)
1	-	-	RASopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.89	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.68		Gain of MoRF binding (P = 0.0092)
MVP		0.82
MPC		1.2
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		0.029	Neutral
Varity_R		0.76
gMVP		0.80
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs727504382; hg19: chr19-4101103; COSMIC: COSV53562848; COSMIC: COSV53562848;