19-4102451-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP3BS2

The NM_030662.4(MAP2K2):​c.453C>G​(p.Asp151Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D151D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 missense, splice_region

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.278
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K2NM_030662.4 linkc.453C>G p.Asp151Glu missense_variant, splice_region_variant Exon 4 of 11 ENST00000262948.10 NP_109587.1 P36507
MAP2K2XM_006722799.3 linkc.453C>G p.Asp151Glu missense_variant, splice_region_variant Exon 4 of 9 XP_006722862.1
MAP2K2XM_047439100.1 linkc.-118C>G splice_region_variant Exon 2 of 9 XP_047295056.1
MAP2K2XM_047439100.1 linkc.-118C>G 5_prime_UTR_variant Exon 2 of 9 XP_047295056.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K2ENST00000262948.10 linkc.453C>G p.Asp151Glu missense_variant, splice_region_variant Exon 4 of 11 1 NM_030662.4 ENSP00000262948.4 P36507

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000346
AC:
5
AN:
1445374
Hom.:
0
Cov.:
31
AF XY:
0.00000418
AC XY:
3
AN XY:
717718
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:
0.00000453
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 16, 2020
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RASopathy Uncertain:1
Jun 25, 2022
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. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 151 of the MAP2K2 protein (p.Asp151Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 543996). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
13
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.33
N
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
0.63
D
MutationAssessor
Benign
0.88
L;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.029
D;D
Polyphen
1.0
D;.
Vest4
0.82
MutPred
0.48
Gain of disorder (P = 0.1258);.;
MVP
0.91
MPC
1.3
ClinPred
0.97
D
GERP RS
-8.4
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.9
Varity_R
0.73
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs17851657; hg19: chr19-4102449; API