rs912154933

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_030662.4(MAP2K2):c.1196C>T(p.Ala399Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A399T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.58

Publications

0 publications found

Variant links:

COSMIC-nc: COSV53567338

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29842633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4 link	c.1196C>T	p.Ala399Val	missense_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	NM_001440688.1 link	c.917C>T	p.Ala306Val	missense_variant	Exon 9 of 9		NP_001427617.1
MAP2K2	NM_001440689.1 link	c.626C>T	p.Ala209Val	missense_variant	Exon 9 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 link	c.1196C>T	p.Ala399Val	missense_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000638

AC:

AN:

156828

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398462

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31644

American (AMR)

AF:

0.00

AC:

AN:

35782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35838

South Asian (SAS)

AF:

0.00

AC:

AN:

79324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079080

Other (OTH)

AF:

0.0000345

AC:

AN:

57946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RASopathy

Uncertain:1

Feb 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAP2K2 protein function. ClinVar contains an entry for this variant (Variation ID: 2081253). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 399 of the MAP2K2 protein (p.Ala399Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

0.064

Eigen_PC

Benign

0.028

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.6

L;.

PhyloP100

9.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.041

D;D

Sift4G

Uncertain

0.025

D;D

Polyphen

0.76

P;.

Vest4

0.40

MutPred

0.12

Loss of methylation at R397 (P = 0.1193);.;

MVP

0.68

MPC

0.57

ClinPred

0.67

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.067

gMVP

0.62

Mutation Taster

=86/14

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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rs912154933

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over