19-4099336-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.784G>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 262 (p.Val262Ile). The filtering allele frequency in gnomAD v4.1.0 is 0.01543% (201/1178752 alleles) in the European (non-Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.219, which predicts no impact on protein function (BP4). This variant has been identified in 4 independent occurrences in patients with disparate phenotypes of RASopathy (PS4 not met; GeneDx, LMM internal data; GTR ID's 26957, 21766; SCV000207950.9, SCV000063182.5). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137966/MONDO:0021060/048

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:3

Conservation

PhyloP100: 2.85

Publications

5 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: ClinGen, Orphanet
cardiofaciocutaneous syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Noonan syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MAP2K2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030662.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP2K2	NM_030662.4	MANE Select	c.784G>A	p.Val262Ile	missense	Exon 7 of 11	NP_109587.1	P36507
MAP2K2	NM_001440689.1		c.214G>A	p.Val72Ile	missense	Exon 5 of 9	NP_001427618.1
MAP2K2	NM_001440688.1		c.705+1683G>A		intron	N/A	NP_001427617.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.784G>A	p.Val262Ile	missense	Exon 7 of 11	ENSP00000262948.4	P36507
MAP2K2	ENST00000945862.1		c.784G>A	p.Val262Ile	missense	Exon 7 of 11	ENSP00000615921.1
MAP2K2	ENST00000897166.1		c.784G>A	p.Val262Ile	missense	Exon 7 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000576

AC:

AN:

243172

AF XY:

0.0000529

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1458164

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

725210

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33434

American (AMR)

AF:

0.0000902

AC:

AN:

44340

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000583

AC:

AN:

85818

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000175

AC:

194

AN:

1110722

Other (OTH)

AF:

0.000216

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000151

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41468

American (AMR)

AF:

0.000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.000116

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

RASopathy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.68

M_CAP

Benign

0.066

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.39

PhyloP100

2.8

PrimateAI

Benign

0.41

PROVEAN

Benign

0.50

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.23

MVP

0.26

MPC

0.36

ClinPred

0.013

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.19

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over