5-88722571-GAAA-GAAAA

Variant names:

• chr5-88722571-G-GA
• rs56660854
• NM_002397.5:c.*32dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002397.5(MEF2C):​c.*32dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 139,172 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 28)
  • Exomes 𝑓: 0.21 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEF2C NM_002397.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.815
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00474 (659/139172) while in subpopulation AFR AF = 0.00835 (323/38676). AF 95% confidence interval is 0.0076. There are 4 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 659 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.*32dupT		3_prime_UTR	Exon 11 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.*32dupT		3_prime_UTR	Exon 12 of 12	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.*32dupT		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.*32dupT		3_prime_UTR	Exon 11 of 11	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.*32dupT		3_prime_UTR	Exon 12 of 12	ENSP00000340874.5	Q06413-5
	MEF2C	ENST00000437473.6	TSL:1	c.*32dupT		3_prime_UTR	Exon 11 of 11	ENSP00000396219.2	Q06413-1

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 661 AN: 139140 Hom.: 4 Cov.: 28

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.000834

Gnomad SAS AF: 0.000915

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00355

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00578

GnomAD2 exomes AF: 0.176 AC: 18154 AN: 103102 AF XY: 0.177

Gnomad AFR exome AF: 0.0618

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.282

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.202

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.205 AC: 189586 AN: 924444 Hom.: 2 Cov.: 8 AF XY: 0.204 AC XY: 93337 AN XY: 457596

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

African (AFR) AF: 0.0825 AC: 2083 AN: 25260

American (AMR) AF: 0.185 AC: 4696 AN: 25410

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 3213 AN: 16262

East Asian (EAS) AF: 0.257 AC: 5599 AN: 21756

South Asian (SAS) AF: 0.219 AC: 12007 AN: 54886

European-Finnish (FIN) AF: 0.150 AC: 5226 AN: 34874

Middle Eastern (MID) AF: 0.129 AC: 495 AN: 3824

European-Non Finnish (NFE) AF: 0.211 AC: 148751 AN: 703954

Other (OTH) AF: 0.197 AC: 7516 AN: 38218

⚠️ 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: 0.00474 AC: 659 AN: 139172 Hom.: 4 Cov.: 28 AF XY: 0.00521 AC XY: 350 AN XY: 67140

African (AFR) AF: 0.00835 AC: 323 AN: 38676

American (AMR) AF: 0.00339 AC: 47 AN: 13870

Ashkenazi Jewish (ASJ) AF: 0.000304 AC: 1 AN: 3288

East Asian (EAS) AF: 0.000837 AC: 4 AN: 4780

South Asian (SAS) AF: 0.000691 AC: 3 AN: 4342

European-Finnish (FIN) AF: 0.0145 AC: 115 AN: 7928

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.00244 AC: 154 AN: 63244

Other (OTH) AF: 0.00575 AC: 11 AN: 1914

Alfa AF: 0.000390 Hom.: 42

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
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;