chr19-4090639-G-A

Position:

chr19-4090639-G-A

Variant summary

Our verdict is Benign. Variant got -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

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:7

Conservation

PhyloP100: 1.11

Variant links:

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 links:

MAP2K2 (HGNC:):

MAP2K2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	11/11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	XM_006722799.3 linkuse as main transcript	c.883C>T	p.Arg295Trp	missense_variant	9/9		XP_006722862.1
MAP2K2	XM_047439100.1 linkuse as main transcript	c.592C>T	p.Arg198Trp	missense_variant	9/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	11/11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152206

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000438

AC:

AN:

164554

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

87172

show subpopulations

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 SAS exome

AF:

0.0000430

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.:

Cov.:

AF XY:

0.000167

AC XY:

116

AN XY:

692960

show subpopulations

Gnomad4 AFR exome

AF:

0.00778

Gnomad4 AMR exome

AF:

0.0000551

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.0000206

Gnomad4 NFE exome

AF:

0.0000129

Gnomad4 OTH exome

AF:

0.000344

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152324

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00721

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.00262

ESP6500AA

AF:

0.00511

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000358

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cardiofaciocutaneous syndrome 4

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2015	p.Arg388Trp in exon 11 of MAP2K2: This variant is not expected to have clinical significance because it has been identified in 0.9% (25/2788) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144383241). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2015	- -

RASopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	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. -

Noonan syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.0096

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.1

L;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.92

P;.

Vest4

0.39

MVP

0.68

MPC

0.71

ClinPred

0.010

GERP RS

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over