rs796052726
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2
The NM_002397.5(MEF2C):c.980G>C(p.Ser327Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000934 in 1,498,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000052 ( 0 hom. )
Consequence
MEF2C
NM_002397.5 missense
NM_002397.5 missense
Scores
3
4
11
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MEF2C
BP4
?
Computational evidence support a benign effect (MetaRNN=0.32069808).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000052 (7/1346118) while in subpopulation AFR AF= 0.000236 (7/29686). AF 95% confidence interval is 0.000111. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEF2C | NM_002397.5 | c.980G>C | p.Ser327Thr | missense_variant | 10/11 | ENST00000504921.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEF2C | ENST00000504921.7 | c.980G>C | p.Ser327Thr | missense_variant | 10/11 | 1 | NM_002397.5 | ||
MEF2C-AS2 | ENST00000657578.1 | n.232-33384C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152046Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000520 AC: 7AN: 1346118Hom.: 0 Cov.: 30 AF XY: 0.00000454 AC XY: 3AN XY: 661496
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74246
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 15, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2018 | The p.S327T variant (also known as c.980G>C), located in coding exon 9 of the MEF2C gene, results from a G to C substitution at nucleotide position 980. The serine at codon 327 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2014 | p.Ser327Thr (AGT>ACT): c.980 G>C in exon 10 of the MEF2C gene (NM_002397.3) A variant of unknown significance has been identified in the MEF2C gene. The S327T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S327T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). - |
Intellectual disability, autosomal dominant 20 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;.;T;.;.;T;T;.;T;.;.;.;.;T;T;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;M;.;M;.;M;.;.;M;M;.;M;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;.;.;.;N;.;N;N;N;.;N;.;.;.;N;.;.;.;.;.
REVEL
Benign
Sift
Benign
D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.
Sift4G
Uncertain
D;D;D;.;.;D;D;T;D;D;D;.;D;D;.;D;D;D;D;.;D;D
Polyphen
D;.;.;.;.;.;D;.;.;.;.;.;.;P;D;.;P;.;.;.;.;.
Vest4
MVP
MPC
2.5
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at