5-88731897-G-C

Variant names:

• chr5-88731897-G-C
• rs79455305
• NM_002397.5:c.642C>G

Variant summary

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

The NM_002397.5(MEF2C):​c.642C>G​(p.Asn214Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,182 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N214N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.642C>G	p.Asn214Lys	missense_variant	Exon 7 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.642C>G	p.Asn214Lys	missense_variant	Exon 7 of 11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454182 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722382

African (AFR) AF: 0.00 AC: 0 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107428

Other (OTH) AF: 0.00 AC: 0 AN: 60000

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.;T;.;.;D;T;.;T;.;.;.;.;D;T;.;.;.;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.93	.;D;.;D;.;D;.;D;.;D;D;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.0	M;.;.;.;M;.;M;.;M;.;.;M;M;M;M;.;M;.;.;.;.;.;.
PhyloP100		0.18
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;.;.;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;.;.;D;D
Sift4G	Benign	0.16	T;T;T;.;.;T;T;T;T;T;T;.;T;T;.;T;T;D;.;T;T;.;T
Polyphen		1.0	D;.;.;.;.;.;D;.;.;.;.;.;.;D;D;.;D;.;.;.;.;.;.
Vest4		0.88
MutPred		0.25		Gain of ubiquitination at N214 (P = 0.0094);.;.;.;Gain of ubiquitination at N214 (P = 0.0094);.;Gain of ubiquitination at N214 (P = 0.0094);.;Gain of ubiquitination at N214 (P = 0.0094);Gain of ubiquitination at N214 (P = 0.0094);Gain of ubiquitination at N214 (P = 0.0094);Gain of ubiquitination at N214 (P = 0.0094);Gain of ubiquitination at N214 (P = 0.0094);Gain of ubiquitination at N214 (P = 0.0094);Gain of ubiquitination at N214 (P = 0.0094);.;Gain of ubiquitination at N214 (P = 0.0094);.;.;.;.;.;.;
MVP		0.91
MPC		2.0
ClinPred		1.0	D
GERP RS		-3.8
PromoterAI		-0.016	Neutral
Varity_R		0.78
gMVP		0.90
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79455305; hg19: chr5-88027714;