19-4101064-G-T

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.660C>A (p.Ile220=) variant in the MAP2K2 gene is 65.271% (3631/5412) of Latino 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/CA137959/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.43 ( 14757 hom., cov: 31)

Exomes 𝑓: 0.47 ( 162519 hom. )

Consequence

MAP2K2
NM_030662.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -0.203

Publications

39 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.660C>A	p.Ile220Ile	synonymous_variant	Exon 6 of 11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	NM_001440688.1 link	c.660C>A	p.Ile220Ile	synonymous_variant	Exon 6 of 9		NP_001427617.1
MAP2K2	NM_001440689.1 link	c.90C>A	p.Ile30Ile	synonymous_variant	Exon 4 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 link	c.660C>A	p.Ile220Ile	synonymous_variant	Exon 6 of 11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65084

AN:

151796

Hom.:

14750

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.454

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.594

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.458

GnomAD2 exomes

AF:

0.478

AC:

98773

AN:

206634

AF XY:

0.473

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.578

Gnomad ASJ exome

AF:

0.537

Gnomad EAS exome

AF:

0.593

Gnomad FIN exome

AF:

0.457

Gnomad NFE exome

AF:

0.477

Gnomad OTH exome

AF:

0.491

GnomAD4 exome

AF:

0.474

AC:

678786

AN:

1433530

Hom.:

162519

Cov.:

AF XY:

0.472

AC XY:

335045

AN XY:

710580

show subpopulations

African (AFR)

AF:

0.258

AC:

8436

AN:

32708

American (AMR)

AF:

0.571

AC:

23029

AN:

40358

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

13774

AN:

25638

East Asian (EAS)

AF:

0.564

AC:

21366

AN:

37900

South Asian (SAS)

AF:

0.398

AC:

32831

AN:

82470

European-Finnish (FIN)

AF:

0.461

AC:

23710

AN:

51448

Middle Eastern (MID)

AF:

0.403

AC:

2177

AN:

5400

European-Non Finnish (NFE)

AF:

0.478

AC:

525477

AN:

1098320

Other (OTH)

AF:

0.472

AC:

27986

AN:

59288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

21123

42246

63369

84492

105615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15566

31132

46698

62264

77830

<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:

0.429

AC:

65113

AN:

151914

Hom.:

14757

Cov.:

AF XY:

0.428

AC XY:

31804

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.274

AC:

11351

AN:

41424

American (AMR)

AF:

0.531

AC:

8112

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

1832

AN:

3468

East Asian (EAS)

AF:

0.594

AC:

3055

AN:

5142

South Asian (SAS)

AF:

0.387

AC:

1866

AN:

4820

European-Finnish (FIN)

AF:

0.461

AC:

4876

AN:

10566

Middle Eastern (MID)

AF:

0.435

AC:

128

AN:

294

European-Non Finnish (NFE)

AF:

0.479

AC:

32516

AN:

67916

Other (OTH)

AF:

0.457

AC:

964

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1829

3659

5488

7318

9147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.441

Hom.:

8604

Bravo

AF:

0.430

Asia WGS

AF:

0.469

AC:

1631

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiofaciocutaneous syndrome 4

Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

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.660C>A (p.Ile220=) variant in the MAP2K2 gene is 65.271% (3631/5412) of Latino 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) -

Baylor Genetics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Variant classified using ACMG guidelines -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Dec 11, 2018

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

-0.39

CADD

Benign

7.2

(source)

DANN

Benign

0.85

PhyloP100

-0.20

PromoterAI

-0.089

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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