rs12521522

Variant names:

• chr5-88816944-T-A
• rs12521522
• NM_002397.5:c.54+6791A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002397.5(MEF2C):​c.54+6791A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 151,942 control chromosomes in the GnomAD database, including 169 homozygotes. 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: 𝑓 0.038 (169 hom., cov: 31)
• Consequence: MEF2C NM_002397.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• Publications: 5 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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.54+6791A>T		intron_variant	Intron 2 of 10	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.54+6791A>T		intron_variant	Intron 2 of 10	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5816 AN: 151824 Hom.: 169 Cov.: 31

Gnomad AFR AF: 0.00901

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0508

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0378

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0383 AC: 5815 AN: 151942 Hom.: 169 Cov.: 31 AF XY: 0.0384 AC XY: 2853 AN XY: 74250

African (AFR) AF: 0.00898 AC: 373 AN: 41522

American (AMR) AF: 0.0229 AC: 349 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3468

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5142

South Asian (SAS) AF: 0.0509 AC: 245 AN: 4816

European-Finnish (FIN) AF: 0.0641 AC: 678 AN: 10578

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0552 AC: 3748 AN: 67880

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0513 Hom.: 34

Bravo AF: 0.0337

Asia WGS AF: 0.0200 AC: 71 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.39
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs12521522; hg19: chr5-88112761;