5-88761275-G-T

Variant names:

• chr5-88761275-G-T
• NM_002397.5:c.312C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002397.5(MEF2C):​c.312C>A​(p.Asp104Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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-AS2 (HGNC:53115): (MEF2C antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.27367997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.312C>A	p.Asp104Glu	missense_variant	Exon 4 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.312C>A	p.Asp104Glu	missense_variant	Exon 4 of 11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 20 Uncertain:1

May 11, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 104 of the MEF2C protein (p.Asp104Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T;.;T;.;T;.;T;.;.;.;.;T;.;T;.;T;.
Eigen	Benign	-0.027
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	.;T;T;.;.;.;T;T;.;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.3	L;L;.;L;L;L;.;.;L;L;L;L;L;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.90	N;N;.;.;N;N;N;N;.;N;.;.;N;.;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.33	T;T;.;.;T;T;T;T;.;T;.;.;T;.;T;T;.
Sift4G	Benign	0.45	T;T;.;.;T;T;T;T;.;T;T;.;T;.;T;T;.
Polyphen		0.027	B;.;.;.;B;.;.;.;.;.;B;B;B;.;.;.;.
Vest4		0.53
MutPred		0.18		Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);Loss of stability (P = 0.0649);
MVP		0.81
MPC		1.5
ClinPred		0.79	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-88057092; COSMIC: COSV60936426; COSMIC: COSV60936426;