rs121908596

Variant names:

• chr15-66436837-G-A
• rs121908596
• NM_002755.4:c.383G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-66436837-G-A
• chr15-66436837-G-C
• chr15-66436837-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_002755.4(MAP2K1):​c.383G>A​(p.Gly128Asp) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86
• Publications: 60 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr15-66436837-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.383G>A	p.Gly128Asp	missense_variant	Exon 3 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.317G>A	p.Gly106Asp	missense_variant	Exon 3 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.317G>A	p.Gly106Asp	missense_variant	Exon 3 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.383G>A	p.Gly128Asp	missense_variant	Exon 3 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.383G>A	p.Gly128Asp	missense_variant	Exon 3 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Uncertain:1

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 128 of the MAP2K1 protein (p.Gly128Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MAP2K1-related conditions (PMID: 31040167). ClinVar contains an entry for this variant (Variation ID: 40746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAP2K1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAP2K1 function (PMID: 12370306). This variant disrupts the p.Gly128 amino acid residue in MAP2K1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1804226, 18039235, 18413255, 21062266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	-0.020	N
PhyloP100		9.9
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.59		Loss of catalytic residue at P124 (P = 0.0836);
MVP		0.98
MPC		2.8
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908596; hg19: chr15-66729175; COSMIC: COSV61068347;