rs796052726

Variant names:

• chr5-88728613-C-A
• rs796052726
• NM_002397.5:c.980G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-88728613-C-A
• chr5-88728613-C-G

Variant summary

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

The NM_002397.5(MEF2C):​c.980G>T​(p.Ser327Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,346,118 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S327T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002397.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	NM_002397.5	MANE Select	c.980G>T	p.Ser327Ile	missense	Exon 10 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.1010G>T	p.Ser337Ile	missense	Exon 11 of 12	NP_001180276.1
	MEF2C	NM_001193350.2		c.980G>T	p.Ser327Ile	missense	Exon 10 of 11	NP_001180279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.980G>T	p.Ser327Ile	missense	Exon 10 of 11	ENSP00000421925.5
	MEF2C	ENST00000340208.9	TSL:1	c.1010G>T	p.Ser337Ile	missense	Exon 11 of 12	ENSP00000340874.5
	MEF2C	ENST00000437473.6	TSL:1	c.980G>T	p.Ser327Ile	missense	Exon 10 of 11	ENSP00000396219.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1346118 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 661496

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29686

American (AMR) AF: 0.00 AC: 0 AN: 30402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23760

East Asian (EAS) AF: 0.00 AC: 0 AN: 34206

South Asian (SAS) AF: 0.00 AC: 0 AN: 67334

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1052354

Other (OTH) AF: 0.00 AC: 0 AN: 55554

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.30		Loss of disorder (P = 0.0036)
MVP		0.76
MPC		2.7
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.91
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs796052726; hg19: chr5-88024430;