5-88729322-G-A

Variant names:

• chr5-88729322-G-A
• rs777826971
• NM_002397.5:c.860C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002397.5(MEF2C):​c.860C>T​(p.Ser287Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S287S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.56
• Publications: 1 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-AS2 (HGNC:53115): (MEF2C antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.860C>T	p.Ser287Leu	missense_variant	Exon 9 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.860C>T	p.Ser287Leu	missense_variant	Exon 9 of 11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 246080 AF XY: 0.00000749

Gnomad AFR exome AF: 0.0000654

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459496 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 725968

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110586

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language Uncertain:2

Oct 30, 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. This sequence change replaces serine with leucine at codon 287 of the MEF2C protein (p.Ser287Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs777826971, ExAC 0.002%). This variant has been observed in an individual with polymicrogyria, microcephaly, and tetraparesis (PMID: 29706646). It is also known as c.890C>T (p.Ser297Leu) in the literature. ClinVar contains an entry for this variant (Variation ID: 438583). 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"). -

Sep 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

this variant was indentified in an individual with malformations of cortical development -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;T;.;.;T;T;.;T;.;.;.;.;T;T;.;.;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D;.;D;.;D;.;D;.;D;D;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M;.;M;.;M;.;.;M;M;.;M;.;.;.;.;.;.;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.8	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.042	D;T;T;.;.;T;D;D;D;T;T;.;D;T;.;T;T;D;D;.;D;T
Polyphen		1.0	D;.;.;.;.;.;D;.;.;.;.;.;.;P;D;.;P;.;.;.;.;.
Vest4		0.86
MutPred		0.21		Loss of disorder (P = 0.0344);.;.;.;Loss of disorder (P = 0.0344);.;Loss of disorder (P = 0.0344);.;Loss of disorder (P = 0.0344);.;Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);.;Loss of disorder (P = 0.0344);.;.;.;.;.;.;.;
MVP		0.70
MPC		2.4
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.36
gMVP		0.80
Mutation Taster		=11/89	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: rs777826971; hg19: chr5-88025139;