rs200371894

Positions:

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.893C>T (p.Pro298Leu) variant in the MAP2K2 gene is 0.953% (68/5776) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA180870/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.00049 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 3 hom. )

Consequence

MAP2K2
NM_030662.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 6.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAP2K2	NM_030662.4 linkuse as main transcript	c.893C>T	p.Pro298Leu	missense_variant	7/11	ENST00000262948.10
MAP2K2	XM_047439100.1 linkuse as main transcript	c.323C>T	p.Pro108Leu	missense_variant	5/9
MAP2K2	XM_006722799.3 linkuse as main transcript	c.705+1792C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.893C>T	p.Pro298Leu	missense_variant	7/11	1	NM_030662.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000964

AC:

218

AN:

226214

Hom.:

AF XY:

0.00101

AC XY:

125

AN XY:

123824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000614

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0111

Gnomad SAS exome

AF:

0.000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00126

GnomAD4 exome

AF:

0.000299

AC:

434

AN:

1451514

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

232

AN XY:

721346

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000922

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00626

Gnomad4 SAS exome

AF:

0.000400

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000885

Gnomad4 OTH exome

AF:

0.000868

GnomAD4 genome

AF:

0.000486

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0110

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000401

Hom.:

Bravo

AF:

0.000457

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000723

AC:

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 22, 2015	p.Pro298Leu in exon 7 of MAP2K2: This variant is not expected to have clinical s ignificance because it has been identified in 1.2% (68/5776) of East Asian chrom osomes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs200371894). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2015	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. -

RASopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.893C>T (p.Pro298Leu) variant in the MAP2K2 gene is 0.953% (68/5776) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 24, 2016

Variant summary: The MAP2K2 c.893C>T (p.Pro298Leu) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 79/73910 control chromosomes (2 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.0117729 (68/5776). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), srong evidence this is a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 22, 2018

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0084

T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

0.95

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.029

D;D

Sift4G

Benign

0.090

T;T

Polyphen

0.34

B;.

Vest4

0.61

MutPred

0.38

Gain of helix (P = 0.0022);.;

MVP

0.85

MPC

0.75

ClinPred

0.060

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.55

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