Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_002397.5(MEF2C):c.1021G>A(p.Ala341Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000507 in 1,380,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
MEF2C (HGNC:6996): (myocyte enhancer factor 2C) This locus encodes a member of the MADS box transcription enhancer factor 2 (MEF2) family of proteins, which play a role in myogenesis. The encoded protein, MEF2 polypeptide C, has both trans-activating and DNA binding activities. This protein may play a role in maintaining the differentiated state of muscle cells. Mutations and deletions at this locus have been associated with severe cognitive disability, stereotypic movements, epilepsy, and cerebral malformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]
Verdict is Likely_benign. Variant got -6 ACMG points.
PP2
Missense variant in the MEF2C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.9523 (above the threshold of 3.09). Trascript score misZ: 4.8218 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 20, complex neurodevelopmental disorder.
BP4
Computational evidence support a benign effect (MetaRNN=0.15200692).
BP6
Variant 5-88728572-C-T is Benign according to our data. Variant chr5-88728572-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211492.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
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