5-88804798-T-C

Variant names:

• chr5-88804798-T-C
• rs1554139870
• NM_002397.5:c.58A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_002397.5(MEF2C):​c.58A>G​(p.Thr20Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T20I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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]

MEF2C Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002397.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-88804798-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521174.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.58A>G	p.Thr20Ala	missense_variant	Exon 3 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.58A>G	p.Thr20Ala	missense_variant	Exon 3 of 11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language Uncertain:1

Apr 19, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MEF2C-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 20 of the MEF2C protein (p.Thr20Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;T;.;.;D;T;.;T;.;.;.;.;D;T;.;.;.;.;.;T;T;.;.;T;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;.;D;.;D;.;D;.;D;D;.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.5	H;H;H;.;H;H;H;.;H;.;.;H;H;H;H;.;H;.;H;.;.;.;.;.;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;D;D;.;D;D;D;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;D;D;.;D;D;D;D;.;D;.
Sift4G	Uncertain	0.0020	D;D;D;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.;D;D;.;.;D;D;.;.;.
Polyphen		0.99	D;.;.;.;.;.;D;.;.;.;.;.;.;D;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.77		Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);Loss of phosphorylation at T20 (P = 0.0196);
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.98
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554139870; hg19: chr5-88100615;