5-88823780-T-A

Variant names:

• chr5-88823780-T-A
• rs876661308
• NM_002397.5:c.9A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 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
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002397.5
• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.9A>T	p.Arg3Ser	missense_variant	Exon 2 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.9A>T	p.Arg3Ser	missense_variant	Exon 2 of 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

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

Dec 20, 2013

Centro Hospitalar S Joao, Faculty of Medicine of Porto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.5
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
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs876661308; hg19: chr5-88119597;