15-66436825-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_002755.4(MAP2K1):​c.371C>G​(p.Pro124Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MAP2K1
NM_002755.4 missense

Scores

12
6
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.79
Variant links:
Genes affected
MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a domain Protein kinase (size 293) in uniprot entity MP2K1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002755.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAP2K1. . Gene score misZ 3.1085 (greater than the threshold 3.09). Trascript score misZ 3.7499 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 3, Costello syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 15-66436825-C-G is Pathogenic according to our data. Variant chr15-66436825-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 372636.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAP2K1NM_002755.4 linkc.371C>G p.Pro124Arg missense_variant 3/11 ENST00000307102.10 NP_002746.1 Q02750-1A4QPA9
MAP2K1NM_001411065.1 linkc.305C>G p.Pro102Arg missense_variant 3/10 NP_001397994.1
MAP2K1XM_011521783.4 linkc.305C>G p.Pro102Arg missense_variant 3/11 XP_011520085.1 B4DFY5
MAP2K1XM_017022411.3 linkc.371C>G p.Pro124Arg missense_variant 3/10 XP_016877900.1 Q02750-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAP2K1ENST00000307102.10 linkc.371C>G p.Pro124Arg missense_variant 3/111 NM_002755.4 ENSP00000302486.5 Q02750-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 11, 2015The novel P124R variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The P124R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P124R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this residue (P124Q and P124L) and in nearby residues (G128V, Y130N, Y130H) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.0
M
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-7.1
D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.91
Loss of catalytic residue at N122 (P = 0.0722);
MVP
0.97
MPC
2.6
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.88
gMVP
0.83

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: rs397516792; hg19: chr15-66729163; COSMIC: COSV61068985; API