rs302478

Variant names:

• chr5-88866859-T-C
• rs302478
• NM_002397.5:c.-143+16096A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002397.5(MEF2C):​c.-143+16096A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 152,322 control chromosomes in the GnomAD database, including 96 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 0.031 (96 hom., cov: 32)
• Consequence: MEF2C NM_002397.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.590
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0311 (4741/152322) while in subpopulation NFE AF = 0.049 (3336/68024). AF 95% confidence interval is 0.0477. There are 96 homozygotes in GnomAd4. There are 2179 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4741 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	NM_002397.5	MANE Select	c.-143+16096A>G		intron	N/A	NP_002388.2
	MEF2C	NM_001193347.1		c.-143+20643A>G		intron	N/A	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.-140+16096A>G		intron	N/A	NP_001180279.1	Q06413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.-143+16096A>G		intron	N/A	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.-143+20643A>G		intron	N/A	ENSP00000340874.5	Q06413-5
	MEF2C	ENST00000437473.6	TSL:1	c.-140+16096A>G		intron	N/A	ENSP00000396219.2	Q06413-1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4742 AN: 152204 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00852

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0296

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

GnomAD4 genome AF: 0.0311 AC: 4741 AN: 152322 Hom.: 96 Cov.: 32 AF XY: 0.0293 AC XY: 2179 AN XY: 74480

African (AFR) AF: 0.00849 AC: 353 AN: 41574

American (AMR) AF: 0.0205 AC: 313 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.0469 AC: 498 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0490 AC: 3336 AN: 68024

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0383 Hom.: 16

Bravo AF: 0.0282

Asia WGS AF: 0.00809 AC: 28 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.86
DANN	Benign	0.78
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs302478; hg19: chr5-88162676;