Genetic Variant MAP2K1:p.Lys5Asn (chr15-66387362-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002755.4(MAP2K1):c.15G>T(p.Lys5Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. K5K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAP2K1
NM_002755.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.85

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39583704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4 link	c.15G>T	p.Lys5Asn	missense_variant	Exon 1 of 11	ENST00000307102.10	NP_002746.1	Q02750-1A4QPA9
MAP2K1	XM_017022411.3 link	c.15G>T	p.Lys5Asn	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.15G>T	p.Lys5Asn	missense_variant	Exon 1 of 11	1	NM_002755.4	ENSP00000302486.5		Q02750-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697732

African (AFR)

AF:

0.00

AC:

AN:

32400

American (AMR)

AF:

0.00

AC:

AN:

37410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25250

East Asian (EAS)

AF:

0.00

AC:

AN:

37108

South Asian (SAS)

AF:

0.00

AC:

AN:

80238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085770

Other (OTH)

AF:

0.00

AC:

AN:

58424

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MAP2K1-related disorder

Uncertain:1

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MAP2K1 c.15G>T variant is predicted to result in the amino acid substitution p.Lys5Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.40

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.5

PhyloP100

4.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.22

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

Sift4G

Benign

0.35

Polyphen

0.91

Vest4

0.38

MutPred

0.39

Loss of methylation at K5 (P = 8e-04);

MVP

0.85

MPC

2.0

ClinPred

0.91

GERP RS

4.0

PromoterAI

-0.076

Neutral

(source)

Varity_R

0.58

gMVP

0.50

Mutation Taster

=86/14

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over