19-4110634-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000262948.10(MAP2K2):​c.325C>G​(p.Pro109Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P109L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAP2K2
ENST00000262948.10 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 9.87
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAP2K2NM_030662.4 linkuse as main transcriptc.325C>G p.Pro109Ala missense_variant 3/11 ENST00000262948.10 NP_109587.1
MAP2K2XM_006722799.3 linkuse as main transcriptc.325C>G p.Pro109Ala missense_variant 3/9 XP_006722862.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAP2K2ENST00000262948.10 linkuse as main transcriptc.325C>G p.Pro109Ala missense_variant 3/111 NM_030662.4 ENSP00000262948 P1
MAP2K2ENST00000394867.9 linkuse as main transcriptn.764C>G non_coding_transcript_exon_variant 2/105
MAP2K2ENST00000599345.1 linkuse as main transcriptn.522C>G non_coding_transcript_exon_variant 3/75
MAP2K2ENST00000687128.1 linkuse as main transcriptn.764C>G non_coding_transcript_exon_variant 2/7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250222
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135386
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460970
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726720
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 16, 2016In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MAP2K2-related disease. This sequence change replaces proline with alanine at codon 109 of the MAP2K2 protein (p.Pro109Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -
Noonan syndrome Benign:1
Likely benign, no assertion criteria providedclinical testingService de Génétique Moléculaire, Hôpital Robert Debré-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T;T
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Uncertain
0.44
T;T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
0.88
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.3
D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.012
D;D
Sift4G
Benign
0.068
T;T
Polyphen
0.10
B;.
Vest4
0.56
MutPred
0.41
Gain of MoRF binding (P = 0.0438);.;
MVP
0.77
MPC
0.52
ClinPred
0.90
D
GERP RS
5.3
Varity_R
0.68
gMVP
0.46

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.

Other links and lift over

dbSNP: rs1060502983; hg19: chr19-4110632; API