5-88722488-CTTT-CTT

Variant names:

• chr5-88722488-CT-C
• rs553216678
• NM_002397.5:c.*115delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002397.5(MEF2C):​c.*115delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 686,466 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.034 (22 hom.)
• Consequence: MEF2C NM_002397.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.63
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00402 (583/145184) while in subpopulation SAS AF = 0.0233 (106/4554). AF 95% confidence interval is 0.0197. There are 2 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 583 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.*115delA		3_prime_UTR	Exon 11 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.*115delA		3_prime_UTR	Exon 12 of 12	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.*115delA		3_prime_UTR	Exon 11 of 11	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.*115delA		3_prime_UTR	Exon 11 of 11	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.*115delA		3_prime_UTR	Exon 12 of 12	ENSP00000340874.5	Q06413-5
	MEF2C	ENST00000437473.6	TSL:1	c.*115delA		3_prime_UTR	Exon 11 of 11	ENSP00000396219.2	Q06413-1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 581 AN: 145152 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00277

Gnomad ASJ AF: 0.00563

Gnomad EAS AF: 0.00260

Gnomad SAS AF: 0.0229

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00261

Gnomad OTH AF: 0.00252

GnomAD4 exome AF: 0.0340 AC: 18400 AN: 541282 Hom.: 22 Cov.: 8 AF XY: 0.0350 AC XY: 9673 AN XY: 276352

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

African (AFR) AF: 0.0339 AC: 438 AN: 12906

American (AMR) AF: 0.0375 AC: 655 AN: 17458

Ashkenazi Jewish (ASJ) AF: 0.0367 AC: 377 AN: 10268

East Asian (EAS) AF: 0.0266 AC: 577 AN: 21722

South Asian (SAS) AF: 0.0646 AC: 2496 AN: 38632

European-Finnish (FIN) AF: 0.0290 AC: 721 AN: 24822

Middle Eastern (MID) AF: 0.0445 AC: 119 AN: 2676

European-Non Finnish (NFE) AF: 0.0313 AC: 12142 AN: 388396

Other (OTH) AF: 0.0359 AC: 875 AN: 24402

⚠️ 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 AF: 0.00402 AC: 583 AN: 145184 Hom.: 2 Cov.: 32 AF XY: 0.00394 AC XY: 278 AN XY: 70522

African (AFR) AF: 0.00546 AC: 217 AN: 39734

American (AMR) AF: 0.00283 AC: 41 AN: 14470

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 19 AN: 3374

East Asian (EAS) AF: 0.00261 AC: 13 AN: 4980

South Asian (SAS) AF: 0.0233 AC: 106 AN: 4554

European-Finnish (FIN) AF: 0.00101 AC: 9 AN: 8896

Middle Eastern (MID) AF: 0.00360 AC: 1 AN: 278

European-Non Finnish (NFE) AF: 0.00261 AC: 172 AN: 66006

Other (OTH) AF: 0.00251 AC: 5 AN: 1992

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.00380

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual Disability, Stereotypic Movements, Epilepsy, and/or Cerebral Malformations (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism

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: rs553216678; hg19: chr5-88018305;