chr19-4101034-C-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.690G>A (p.Thr230=) variant in the MAP2K2 gene is 0.1273% for Latino chromosomes by the Exome Aggregation Consortium (3/642 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA291996/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

MAP2K2
NM_030662.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: -5.29

Publications

4 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.690G>A	p.Thr230Thr	synonymous_variant	Exon 6 of 11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	NM_001440688.1 link	c.690G>A	p.Thr230Thr	synonymous_variant	Exon 6 of 9		NP_001427617.1
MAP2K2	NM_001440689.1 link	c.120G>A	p.Thr40Thr	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.690G>A	p.Thr230Thr	synonymous_variant	Exon 6 of 11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000328

AC:

AN:

176730

AF XY:

0.000277

show subpopulations

Gnomad AFR exome

AF:

0.0000987

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000786

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

174

AN:

1412080

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

697942

show subpopulations

African (AFR)

AF:

0.000187

AC:

AN:

32064

American (AMR)

AF:

0.00138

AC:

AN:

37074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25346

East Asian (EAS)

AF:

0.0000545

AC:

AN:

36698

South Asian (SAS)

AF:

0.000361

AC:

AN:

80410

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50218

Middle Eastern (MID)

AF:

0.000435

AC:

AN:

4598

European-Non Finnish (NFE)

AF:

0.0000727

AC:

AN:

1087128

Other (OTH)

AF:

0.0000683

AC:

AN:

58544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000789

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41476

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000149

Hom.:

Bravo

AF:

0.000215

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2018

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency of the c.690G>A (p.Thr230=) variant in the MAP2K2 gene is 0.1273% for Latino chromosomes by the Exome Aggregation Consortium (3/642 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). -

not specified

Benign:1

Apr 09, 2014

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. -

MAP2K2-related disorder

Benign:1

Apr 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Apr 15, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.690G>A affects a non-conserved nucleotide resulting in a synonymous change. 5/5 programs in Alamut predict that this variant does not affect normal splicing. This variant was found in 7/24886 control chromosomes in ExAC at a frequency of 0.0002813 (including one homozygote), which sifnificantly exceeds the maximal expected frequency of a pathogenic allele (0.0000025), suggesting this variant is a benign polymorphism. This variant, to our knowledge, has not been reported in affected individuals via publicaitons. One linical laboratory classified this variant as benign. Taken together, this variant was classified as benign. -

Cardiovascular phenotype

Benign:1

Aug 14, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiofaciocutaneous syndrome 4

Benign:1

May 10, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.11

(source)

DANN

Benign

0.59

PhyloP100

-5.3

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(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