15-66435117-G-T

Position:

• chr15-66435117-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_002755.4(MAP2K1):​c.171G>T​(p.Lys57Asn) variant causes a missense change involving the alteration of a non-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
• Clinical Significance: Pathogenic criteria provided, single submitter P:5 O:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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, 0.866
• PP5: Variant 15-66435117-G-T is Pathogenic according to our data. Variant chr15-66435117-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 223140.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.171G>T	p.Lys57Asn	missense_variant	2/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.105G>T	p.Lys35Asn	missense_variant	2/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.105G>T	p.Lys35Asn	missense_variant	2/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.171G>T	p.Lys57Asn	missense_variant	2/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.171G>T	p.Lys57Asn	missense_variant	2/11	1	NM_002755.4	ENSP00000302486	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Melorheostosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 23, 2020

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Apr 26, 2021

This variant has been previously reported in several unrelated individuals with arteriovenous malformations, and in vitro functional studies have demonstrated that the p.Lys57Asn substitution results in activation of downstream signaling (PMID: 28190454, PMID: 29461977). This variant has not been observed in large population studies (Genome Aggregation Database v2.1.1). -

Non-small cell lung carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Cardio-facio-cutaneous syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.36		Loss of ubiquitination at K57 (P = 0.0027);
MVP		0.96
MPC		2.7
ClinPred		0.99	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94

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

Other links and lift over

dbSNP: rs869025608; hg19: chr15-66727455; COSMIC: COSV61068581;