rs1555416037

Variant names:

• chr15-66435071-TTGA-T
• rs1555416037
• NM_002755.4:c.129_131delTGA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_002755.4(MAP2K1):​c.129_131delTGA​(p.Asp43del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002755.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002755.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.129_131delTGA	p.Asp43del	disruptive_inframe_deletion	Exon 2 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.63_65delTGA	p.Asp21del	disruptive_inframe_deletion	Exon 2 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.63_65delTGA	p.Asp21del	disruptive_inframe_deletion	Exon 2 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.129_131delTGA	p.Asp43del	disruptive_inframe_deletion	Exon 2 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.129_131delTGA	p.Asp43del	disruptive_inframe_deletion	Exon 2 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Uncertain:1

Jun 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.129_131delTGA, results in the deletion of 1 amino acid of the MAP2K1 protein (p.Asp43del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MAP2K1-related disease. In summary, this variant has uncertain impact on MAP2K1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

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

Other links and lift over

dbSNP: rs1555416037; hg19: chr15-66727409;