19-4099254-CCTT-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2
The NM_030662.4(MAP2K2):c.863_865delAAG(p.Glu288del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000255 in 1,605,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_030662.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAP2K2 | NM_030662.4 | c.863_865delAAG | p.Glu288del | disruptive_inframe_deletion | Exon 7 of 11 | ENST00000262948.10 | NP_109587.1 | |
MAP2K2 | XM_047439100.1 | c.293_295delAAG | p.Glu98del | disruptive_inframe_deletion | Exon 5 of 9 | XP_047295056.1 | ||
MAP2K2 | XM_006722799.3 | c.705+1762_705+1764delAAG | intron_variant | Intron 6 of 8 | XP_006722862.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000475 AC: 11AN: 231466Hom.: 0 AF XY: 0.0000634 AC XY: 8AN XY: 126248
GnomAD4 exome AF: 0.0000193 AC: 28AN: 1453538Hom.: 0 AF XY: 0.0000263 AC XY: 19AN XY: 722548
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74516
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: GnomAd 19:4099252 CCTT / C: Latino 6/32102; well conserved; Not in ClinVar, Pubmed, Google search or HGMD -
Variant summary: The MAP2K2 c.863_865delAAG (p.Glu288del) variant involves deletion of three adjacent nucleotides. One in silico tool predicts a damaging outcome for this variant. This variant was found in 12/227546 control chromosomes at a frequency of 0.0000527, which is approximately 21 times the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. One internal LCA sample also carried a pathogenic variant in PTPN11 c.172A>G/p.Asn58Asp (scored as DV), further supporting the benign nature of this variant. Taken together, this variant is classified as likely benign. -
not provided Uncertain:1Benign:1
BP3 -
In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 27060149) -
RASopathy Uncertain:1
This variant, c.863_865del, results in the deletion of 1 amino acid(s) of the MAP2K2 protein (p.Glu288del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763469132, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 503543). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at