rs373579939

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The ENST00000262948.10(MAP2K2):c.289A>T(p.Ile97Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I97M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

MAP2K2
ENST00000262948.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.54

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 Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4 linkuse as main transcript	c.289A>T	p.Ile97Phe	missense_variant	2/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.289A>T	p.Ile97Phe	missense_variant	2/9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.289A>T	p.Ile97Phe	missense_variant	2/11	1	NM_030662.4	ENSP00000262948	P1
MAP2K2	ENST00000394867.9 linkuse as main transcript	n.728A>T		non_coding_transcript_exon_variant	1/10	5
MAP2K2	ENST00000599345.1 linkuse as main transcript	n.486A>T		non_coding_transcript_exon_variant	2/7	5
MAP2K2	ENST00000687128.1 linkuse as main transcript	n.728A>T		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250620

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2014	This variant is denoted c.289 A>T at the cDNA level or p.Ile97Phe (I97F) at the protein level. The I97F missense change has not been previously reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. The I97F missense change is a conservative amino acid substitution as both Isoleucine and Phenylalanine are neutral and non-polar resiudes. The residue at which this substitution occurs is conserved in mammals. The I97F variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In silico models are discordant in their assessment of the pathogenicity of the variant. Another missense mutation at a nearby residue (A80T) has been reported. Although the majority of missense changes in MAP2K2 are pathogenic mutations, the potential for benign coding variants to exist in this gene must be considered. The variant is found in NOONAN panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 08, 2022	PP3 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ile97Phe vari ant in MAP2K2 has now been identified by our laboratory in 2 individuals with cl inical features of a RASopathy disorder and a reportedly unaffected parent. It h as also been identified in 1/65212 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373579939). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conser vation analysis do not provide strong support for or against an impact to the pr otein. In summary, although the clinical significance of the p.Ile97Phe variant is uncertain, identification in an unaffected parent suggest that this variant i s more likely benign. -

RASopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 97 of the MAP2K2 protein (p.Ile97Phe). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt MAP2K2 function. ClinVar contains an entry for this variant (Variation ID: 46232). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. This variant is present in population databases (rs373579939, gnomAD 0.002%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.043

Polyphen

0.79

Vest4

0.70

MVP

0.80

MPC

1.0

ClinPred

0.94

GERP RS

3.6

Varity_R

0.77

gMVP

0.64

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