5-88720336-A-ATT

Variant summary

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

The NM_002397.5(MEF2C):c.*2267_*2268insAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.025 (59 hom., cov: 0)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: MEF2C NM_002397.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00700

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 = 0.0249 (3719/149228) while in subpopulation AFR AF= 0.0422 (1723/40816). AF 95% confidence interval is 0.0406. There are 59 homozygotes in gnomad4. There are 1729 alleles in male gnomad4 subpopulation. Median coverage is 0. 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 3710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEF2C	NM_002397.5	c.*2267_*2268insAA		3_prime_UTR_variant	11/11	ENST00000504921.7
MEF2C-AS2	NR_146284.1	n.256-2277_256-2276dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEF2C	ENST00000504921.7	c.*2267_*2268insAA		3_prime_UTR_variant	11/11	1	NM_002397.5
MEF2C-AS2	ENST00000657578.1	n.232-41650_232-41649dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3710 AN: 149124 Hom.: 59 Cov.: 0

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00350

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.00973

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.0137 AC: 5 AN: 364 Hom.: 0 Cov.: 0 AF XY: 0.0223 AC XY: 5 AN XY: 224

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0249 AC: 3719 AN: 149228 Hom.: 59 Cov.: 0 AF XY: 0.0238 AC XY: 1729 AN XY: 72714

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.00350

Gnomad4 EAS AF: 0.00118

Gnomad4 SAS AF: 0.0414

Gnomad4 FIN AF: 0.00973

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0213

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

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3841444; hg19: chr5-88016153;