rs768570497
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_002397.5(MEF2C):c.1247C>T(p.Ala416Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,712 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
MEF2C
NM_002397.5 missense
NM_002397.5 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: 7.65
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=0.2208811).
BS2
?
High AC in GnomAdExome4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEF2C | NM_002397.5 | c.1247C>T | p.Ala416Val | missense_variant | 11/11 | ENST00000504921.7 | |
MEF2C-AS2 | NR_146284.1 | n.411G>A | non_coding_transcript_exon_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEF2C | ENST00000504921.7 | c.1247C>T | p.Ala416Val | missense_variant | 11/11 | 1 | NM_002397.5 | ||
MEF2C-AS2 | ENST00000657578.1 | n.232-39218G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461712Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727138
GnomAD4 exome
AF:
AC:
9
AN:
1461712
Hom.:
Cov.:
33
AF XY:
AC XY:
4
AN XY:
727138
Gnomad4 AFR exome
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Gnomad4 SAS exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Alfa
AF:
Hom.:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 20 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 22, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 538815). This variant has not been reported in the literature in individuals affected with MEF2C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 416 of the MEF2C protein (p.Ala416Val). - |
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
Uncertain
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
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.;.;.;N;.;.;.;.;N;.;.;.;.;.;.;.
REVEL
Benign
Sift
Benign
T;T;T;.;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.
Sift4G
Benign
T;T;T;.;.;T;T;T;T;T;.;T;T;.;T;T;.;T;T
Polyphen
P;.;.;.;.;.;P;.;.;.;.;.;B;P;.;B;.;.;.
Vest4
MutPred
Loss of catalytic residue at A416 (P = 0.1315);.;.;.;.;.;Loss of catalytic residue at A416 (P = 0.1315);.;.;.;.;.;.;Loss of catalytic residue at A416 (P = 0.1315);.;.;.;.;.;
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at