15-66387358-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002755.4(MAP2K1):c.11A>G(p.Lys4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,230 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K4K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MAP2K1
NM_002755.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.52

Publications

0 publications found

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]

MAP2K1 Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
cardiofaciocutaneous syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
Noonan syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MAP2K1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18643251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4 link	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 11	ENST00000307102.10	NP_002746.1	Q02750-1A4QPA9
MAP2K1	XM_017022411.3 link	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 10		XP_016877900.1	Q02750-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10 link	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 11	1	NM_002755.4	ENSP00000302486.5		Q02750-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000116

AC:

AN:

172566

AF XY:

0.0000218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000757

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1411230

Hom.:

Cov.:

AF XY:

0.00000574

AC XY:

AN XY:

697246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32342

American (AMR)

AF:

0.0000805

AC:

AN:

37272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.00

AC:

AN:

37052

South Asian (SAS)

AF:

0.00

AC:

AN:

80164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1085286

Other (OTH)

AF:

0.00

AC:

AN:

58388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000113

ExAC

AF:

0.0000258

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 27, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.11A>G (p.Lys4Arg) in MAP2K1 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain and no functional studies implying the impact of this varian ton protein function have been published at the time of evaluation. The variant is absent from the control population dataset of ExAC (0/ 21980 chrs tested). Small numbers of sample in ExAC database indicate a low coverage site, therefore this data should be reviewed with caution. The variant is present in control population of gnomAD at a frequency of 0.00001208 (2/ 165522 chrs tested), which exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.0000025). The presence of the variant in presumably unaffected individual in gnomAD suggests a benign outcome, as mutations in MAP2K1 are extremely rare in hematologic malignancy (COSMIC). The variant has not, to our knowledge, been reported in affected individuals via published reports or by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more evidence becomes available. -

Dec 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MAP2K1 c.11A>G; p.Lys4Arg variant (rs761150136), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 496174). This variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.371). Due to limited information, the clinical significance of this variant is uncertain at this time. -

RASopathy

Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 4 of the MAP2K1 protein (p.Lys4Arg). This variant is present in population databases (rs761150136, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MAP2K1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496174). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAP2K1 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.32

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.39

MutationAssessor

Benign

-0.41

PhyloP100

4.5

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.030

REVEL

Uncertain

0.37

Sift

Benign

1.0

Sift4G

Benign

0.64

Polyphen

0.0010

Vest4

0.31

MutPred

0.33

Loss of methylation at K4 (P = 0.0097);

MVP

0.76

MPC

1.1

ClinPred

0.18

GERP RS

4.0

PromoterAI

0.060

Neutral

(source)

Varity_R

0.19

gMVP

0.29

Mutation Taster

=89/11

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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15-66387358-A-G

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