rs797045703

Variant names:

• chr5-88728572-C-G
• NM_002397.5:c.1021G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-88728572-C-G
• chr5-88728572-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002397.5(MEF2C):​c.1021G>C​(p.Ala341Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,380,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEF2C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.9523 (above the threshold of 3.09). Trascript score misZ: 4.8218 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 20, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29657763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.1021G>C	p.Ala341Pro	missense_variant	Exon 10 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.1021G>C	p.Ala341Pro	missense_variant	Exon 10 of 11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1380490 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 680350

Gnomad4 AFR exome AF: 0.00

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: 0.00000187

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;T;.;.;T;T;.;T;.;.;.;.;T;T;.;.;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	.;D;.;D;.;D;.;D;.;D;D;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;.;L;.;L;.;L;.;.;L;L;.;L;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;N;N;.;.;.;N;.;N;N;N;.;N;.;.;.;N;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.25	T;T;T;.;.;.;T;.;T;T;T;.;T;.;.;.;T;.;.;.;.;.
Sift4G	Benign	0.27	T;T;T;.;.;T;T;T;T;T;T;.;T;T;.;T;T;T;T;.;T;T
Polyphen		0.82	P;.;.;.;.;.;P;.;.;.;.;.;.;D;P;.;D;.;.;.;.;.
Vest4		0.64
MutPred		0.35		Gain of disorder (P = 0.0497);.;.;.;Gain of disorder (P = 0.0497);.;Gain of disorder (P = 0.0497);.;Gain of disorder (P = 0.0497);.;Gain of disorder (P = 0.0497);Gain of disorder (P = 0.0497);Gain of disorder (P = 0.0497);.;Gain of disorder (P = 0.0497);.;.;.;.;.;.;.;
MVP		0.63
MPC		2.7
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.32
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-88024389;