5-88722571-GAA-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002397.5(MEF2C):c.*31_*32del 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

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

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 598 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEF2C	NM_002397.5	c.*31_*32del		3_prime_UTR_variant	11/11	ENST00000504921.7
MEF2C-AS2	NR_146284.1	n.256-41_256-40del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEF2C	ENST00000504921.7	c.*31_*32del		3_prime_UTR_variant	11/11	1	NM_002397.5
MEF2C-AS2	ENST00000657578.1	n.232-39414_232-39413del		intron_variant, non_coding_transcript_variant

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

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

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000476

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000380

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.000581

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00429 AC: 598 AN: 139378 Hom.: 7 Cov.: 28 AF XY: 0.00422 AC XY: 284 AN XY: 67260

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00245

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000252

Gnomad4 OTH AF: 0.00313

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual Disability, Stereotypic Movements, Epilepsy, and/or Cerebral Malformations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs56660854; hg19: chr5-88018388;