rs397516793

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_002755.4(MAP2K1):​c.388T>A​(p.Tyr130Asn) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y130C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MAP2K1
NM_002755.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 7.90
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 13 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-66436843-A-G is described in Lovd as [Pathogenic].
PP2
Missense variant in the MAP2K1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 3.1085 (above the threshold of 3.09). Trascript score misZ: 3.7499 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.992
PP5
Variant 15-66436842-T-A is Pathogenic according to our data. Variant chr15-66436842-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 636238.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K1NM_002755.4 linkc.388T>A p.Tyr130Asn missense_variant Exon 3 of 11 ENST00000307102.10 NP_002746.1 Q02750-1A4QPA9
MAP2K1NM_001411065.1 linkc.322T>A p.Tyr108Asn missense_variant Exon 3 of 10 NP_001397994.1
MAP2K1XM_011521783.4 linkc.322T>A p.Tyr108Asn missense_variant Exon 3 of 11 XP_011520085.1 B4DFY5
MAP2K1XM_017022411.3 linkc.388T>A p.Tyr130Asn missense_variant Exon 3 of 10 XP_016877900.1 Q02750-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K1ENST00000307102.10 linkc.388T>A p.Tyr130Asn missense_variant Exon 3 of 11 1 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:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiofaciocutaneous syndrome 3 Pathogenic:1Other:1
-
GenomeConnect - CFC International
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 09-28-2018 by Lab or GTR ID 1006. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

Jul 13, 2018
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A mosaic de novo c.388T>A (p.Y130N) pathogenic variant in the MAP2K1 gene was detected by exome sequencing and confirmed by Sanger sequencing. The c.388T>A (p.Y130N) variant has been previously reported as disease-causing in one patient with cardiofaciocutaneous syndrome [PMID 18413255] and is absent in the general population (gnomAD database). In addition, allelic variants of c.389A>G (p.Y130C) and c.388T>C (p.Y130H) are both pathogenic variants previously reported in multiple affected patients. Functional studies showed protein with p.Y130C variant has increased kinase activity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.47
T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.3
M
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-8.0
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.96
Gain of phosphorylation at Y134 (P = 0.2896);
MVP
0.96
MPC
3.2
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.99
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs397516793; hg19: chr15-66729180; COSMIC: COSV61071862; API