chr19-4102451-G-A

Variant names:

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.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European 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/CA137943/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.14 ( 1972 hom., cov: 33)

Exomes 𝑓: 0.19 ( 27044 hom. )

Consequence

MAP2K2
NM_030662.4 splice_region, synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: -0.278

Publications

30 publications found

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 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

MAP2K2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4 link	c.453C>T	p.Asp151Asp	splice_region_variant, synonymous_variant	Exon 4 of 11	ENST00000262948.10	NP_109587.1	P36507

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 link	c.453C>T	p.Asp151Asp	splice_region_variant, synonymous_variant	Exon 4 of 11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21512

AN:

152112

Hom.:

1967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0441

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.0430

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.154

GnomAD2 exomes

AF:

0.163

AC:

36340

AN:

222968

AF XY:

0.170

show subpopulations

Gnomad AFR exome

AF:

0.0416

Gnomad AMR exome

AF:

0.0893

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.0350

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.188

AC:

271555

AN:

1443232

Hom.:

27044

Cov.:

AF XY:

0.189

AC XY:

135803

AN XY:

716686

show subpopulations

African (AFR)

AF:

0.0397

AC:

1323

AN:

33312

American (AMR)

AF:

0.0933

AC:

3950

AN:

42358

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

5670

AN:

25764

East Asian (EAS)

AF:

0.0531

AC:

2083

AN:

39218

South Asian (SAS)

AF:

0.208

AC:

17425

AN:

83738

European-Finnish (FIN)

AF:

0.186

AC:

9342

AN:

50344

Middle Eastern (MID)

AF:

0.216

AC:

1237

AN:

5740

European-Non Finnish (NFE)

AF:

0.200

AC:

220079

AN:

1103018

Other (OTH)

AF:

0.175

AC:

10446

AN:

59740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

10974

21948

32921

43895

54869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7536

15072

22608

30144

37680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.141

AC:

21533

AN:

152230

Hom.:

1972

Cov.:

AF XY:

0.140

AC XY:

10386

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0441

AC:

1834

AN:

41550

American (AMR)

AF:

0.128

AC:

1953

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

796

AN:

3468

East Asian (EAS)

AF:

0.0431

AC:

223

AN:

5176

South Asian (SAS)

AF:

0.202

AC:

972

AN:

4822

European-Finnish (FIN)

AF:

0.176

AC:

1873

AN:

10612

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.196

AC:

13305

AN:

67982

Other (OTH)

AF:

0.160

AC:

339

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

930

1860

2791

3721

4651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.176

Hom.:

1468

Bravo

AF:

0.132

Asia WGS

AF:

0.143

AC:

501

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 29, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

RASopathy

Benign:3

May 09, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency of the c.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European 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) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Baylor Genetics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Variant classified using ACMG guidelines -

Cardiofaciocutaneous syndrome 4

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Jan 21, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.24

(source)

DANN

Benign

0.77

PhyloP100

-0.28

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over