rs876661308

Positions:

• chr5-88823780-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_002397.5(MEF2C):​c.9A>T​(p.Arg3Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.55

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain MADS-box (size 54) in uniprot entity MEF2C_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_002397.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEF2C. . Gene score misZ 3.9523 (greater than the threshold 3.09). Trascript score misZ 4.8218 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 20, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 5-88823780-T-A is Pathogenic according to our data. Variant chr5-88823780-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 218315.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.9A>T	p.Arg3Ser	missense_variant	2/11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.9A>T	p.Arg3Ser	missense_variant	2/11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 20 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centro Hospitalar S Joao, Faculty of Medicine of Porto

Dec 20, 2013

This variant in the MEF2C gene, not described in the literature before, was identified in a 10 year-old boy with severe psychomotor delay, epilepsy, generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphism. This variant is predicted to be pathogenic (according to Mutation taster (MT), PolyPhen-2 (PP-2) and Sorts Intolerant From Tolerant (SIFT). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;T;.;.;D;T;.;T;.;.;.;.;D;T;.;.;.;.;.;T;T;.;.;T;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	.;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	0.81	D
MetaRNN	Pathogenic	0.91	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	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;H;.;H;H;H;.;H;.;.;H;H;H;H;.;H;.;H;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;D;D;.;D;D;D;D;.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;D;D;.;D;D;D;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.;D;D;.;.;D;D;.;.;.
Polyphen		0.31	B;.;.;.;.;.;B;.;.;.;.;.;.;D;B;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.96
MutPred		0.61		Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);Gain of ubiquitination at K4 (P = 0.0314);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs876661308; hg19: chr5-88119597;