chr19-4090607-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1194C>T (p.Thr398=) variant in the MAP2K2 gene is 0.159% (19/7836) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137913/MONDO:0021060/004
Frequency
Consequence
NM_030662.4 synonymous
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.1194C>T | p.Thr398Thr | synonymous_variant | Exon 11 of 11 | ENST00000262948.10 | NP_109587.1 | |
MAP2K2 | XM_006722799.3 | c.915C>T | p.Thr305Thr | synonymous_variant | Exon 9 of 9 | XP_006722862.1 | ||
MAP2K2 | XM_047439100.1 | c.624C>T | p.Thr208Thr | synonymous_variant | Exon 9 of 9 | XP_047295056.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000510 AC: 80AN: 156826Hom.: 0 AF XY: 0.000482 AC XY: 40AN XY: 82976
GnomAD4 exome AF: 0.000188 AC: 263AN: 1398640Hom.: 1 Cov.: 31 AF XY: 0.000193 AC XY: 133AN XY: 690066
GnomAD4 genome AF: 0.000223 AC: 34AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74374
ClinVar
Submissions by phenotype
not provided Benign:2
Variant summary: The c.1194C>T (p.Thr398=) in MAP2K2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.00097 (19/19528chrs tested) exclusively in individuals of European origin (0.0024; 19/7836). However ExAC includes a warning note, this variant is only covered in 9764 individuals (adjusted allele number = 19528). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site. Regardless, this frequency exceeds the maximal expected frequency of a pathogenic allele (0.0000025) in this gene. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but was cited as Likely Benign by reputable databases/clinical laboratory. Taking together, based on the prevalence in the general population, the synonymous nature of the variant and the lack of predicted effect on splicing, the variant was classified as Benign. -
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RASopathy Benign:2
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The filtering allele frequency of the c.1194C>T (p.Thr398=) variant in the MAP2K2 gene is 0.159% (19/7836) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -
not specified Benign:1
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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