NM_030662.4:c.1162C>T

Variant names:

• chr19-4090639-G-A
• rs144383241
• NM_030662.4:c.1162C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1162C>T (p.Arg388Trp) variant in the MAP2K2 gene is 0.125% for African chromosomes by the Exome Aggregation Consortium (25/2788 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case-level data available: SCV000204180.4; SCV000252871.4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180895/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:7
• Conservation: PhyloP100: 1.11
• Publications: 4 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: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	NM_030662.4	MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 11 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.883C>T	p.Arg295Trp	missense	Exon 9 of 9	NP_001427617.1
	MAP2K2	NM_001440689.1		c.592C>T	p.Arg198Trp	missense	Exon 9 of 9	NP_001427618.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 11 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.1351C>T	p.Arg451Trp	missense	Exon 11 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.1321C>T	p.Arg441Trp	missense	Exon 11 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000438 AC: 72 AN: 164554 AF XY: 0.000287

Gnomad AFR exome AF: 0.00713

Gnomad AMR exome AF: 0.0000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000307

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000204 AC: 286 AN: 1403656 Hom.: 1 Cov.: 32 AF XY: 0.000167 AC XY: 116 AN XY: 692960

African (AFR) AF: 0.00778 AC: 248 AN: 31882

American (AMR) AF: 0.0000551 AC: 2 AN: 36290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 36228

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79670

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1081908

Other (OTH) AF: 0.000344 AC: 20 AN: 58166

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00191 AC XY: 142 AN XY: 74478

African (AFR) AF: 0.00721 AC: 300 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000384 Hom.: 1

Bravo AF: 0.00262

ESP6500AA AF: 0.00511 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000358 AC: 41

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Cardiofaciocutaneous syndrome 4 (2)
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Noonan syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.92	P
Vest4		0.39
MVP		0.68
MPC		0.71
ClinPred		0.010	T
GERP RS		0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.43
Mutation Taster		=79/21	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: rs144383241; hg19: chr19-4090637; COSMIC: COSV53570890;