5-88722571-GAAA-GA

Variant names:

• chr5-88722571-GAA-G
• rs56660854
• NM_002397.5:c.*31_*32delTT

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.*31_*32delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,316,828 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (7 hom., cov: 28)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: MEF2C NM_002397.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• 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 afr. GnomAd4 allele frequency = 0.00429 (598/139378) while in subpopulation AFR AF = 0.014 (542/38684). AF 95% confidence interval is 0.013. There are 7 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 28. 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 598 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.*31_*32delTT		3_prime_UTR	Exon 11 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.*31_*32delTT		3_prime_UTR	Exon 12 of 12	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.*31_*32delTT		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.*31_*32delTT		3_prime_UTR	Exon 11 of 11	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.*31_*32delTT		3_prime_UTR	Exon 12 of 12	ENSP00000340874.5	Q06413-5
	MEF2C	ENST00000437473.6	TSL:1	c.*31_*32delTT		3_prime_UTR	Exon 11 of 11	ENSP00000396219.2	Q06413-1

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 598 AN: 139346 Hom.: 7 Cov.: 28

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.00315

GnomAD2 exomes AF: 0.00413 AC: 426 AN: 103102 AF XY: 0.00331

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00286

GnomAD4 exome AF: 0.00105 AC: 1234 AN: 1177450 Hom.: 2 AF XY: 0.00102 AC XY: 599 AN XY: 586270

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

African (AFR) AF: 0.0183 AC: 502 AN: 27502

American (AMR) AF: 0.00130 AC: 45 AN: 34598

Ashkenazi Jewish (ASJ) AF: 0.000476 AC: 10 AN: 21010

East Asian (EAS) AF: 0.00 AC: 0 AN: 34454

South Asian (SAS) AF: 0.000380 AC: 27 AN: 71104

European-Finnish (FIN) AF: 0.00150 AC: 65 AN: 43446

Middle Eastern (MID) AF: 0.00151 AC: 7 AN: 4628

European-Non Finnish (NFE) AF: 0.000581 AC: 518 AN: 891346

Other (OTH) AF: 0.00122 AC: 60 AN: 49362

⚠️ 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: 0.00429 AC: 598 AN: 139378 Hom.: 7 Cov.: 28 AF XY: 0.00422 AC XY: 284 AN XY: 67260

African (AFR) AF: 0.0140 AC: 542 AN: 38684

American (AMR) AF: 0.00245 AC: 34 AN: 13886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3292

East Asian (EAS) AF: 0.00 AC: 0 AN: 4790

South Asian (SAS) AF: 0.00 AC: 0 AN: 4342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.000252 AC: 16 AN: 63390

Other (OTH) AF: 0.00313 AC: 6 AN: 1916

Alfa AF: 0.00 Hom.: 42

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual Disability, Stereotypic Movements, Epilepsy, and/or Cerebral Malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
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: rs56660854; hg19: chr5-88018388;