rs796052726

Positions:

• chr5-88728613-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_002397.5(MEF2C):​c.980G>C​(p.Ser327Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000934 in 1,498,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -9 ACMG points.

• 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). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, autosomal dominant 20, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32069808).
• BP6: Variant 5-88728613-C-G is Benign according to our data. Variant chr5-88728613-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206127.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000052 (7/1346118) while in subpopulation AFR AF= 0.000236 (7/29686). AF 95% confidence interval is 0.000111. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.980G>C	p.Ser327Thr	missense_variant	10/11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.980G>C	p.Ser327Thr	missense_variant	10/11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000520 AC: 7 AN: 1346118 Hom.: 0 Cov.: 30 AF XY: 0.00000454 AC XY: 3 AN XY: 661496

Gnomad4 AFR exome AF: 0.000236

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74246

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 15, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2014

p.Ser327Thr (AGT>ACT): c.980 G>C in exon 10 of the MEF2C gene (NM_002397.3) A variant of unknown significance has been identified in the MEF2C gene. The S327T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S327T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, autosomal dominant 20 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;T;.;.;T;T;.;T;.;.;.;.;T;T;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;D;.;D;.;D;.;D;D;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M;.;.;.;M;.;M;.;M;.;.;M;M;.;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N;N;N;.;.;.;N;.;N;N;N;.;N;.;.;.;N;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.038	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.047	D;D;D;.;.;D;D;T;D;D;D;.;D;D;.;D;D;D;D;.;D;D
Polyphen		0.98	D;.;.;.;.;.;D;.;.;.;.;.;.;P;D;.;P;.;.;.;.;.
Vest4		0.55
MVP		0.72
MPC		2.5
ClinPred		0.25	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.81

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: rs796052726; hg19: chr5-88024430;