chr5-88883337-AAGG-A

Position:

• chr5-88883337-AAGG-A

Variant summary

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

The ENST00000437473.6(MEF2C):​c.-525_-523delCCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 151,550 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 27)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: MEF2C ENST00000437473.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.139

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-AS1 (HGNC:48908): (MEF2C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (380/150158) while in subpopulation NFE AF= 0.00211 (142/67394). AF 95% confidence interval is 0.00182. There are 3 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 380 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2C	XM_047417217.1	c.-525_-523delCCT		5_prime_UTR_variant	3/13		XP_047273173.1
MEF2C	XM_047417181.1	c.-525_-523delCCT		5_prime_UTR_variant	3/13		XP_047273137.1
MEF2C	XM_047417182.1	c.-528_-526delCCT		5_prime_UTR_variant	3/13		XP_047273138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000437473.6	c.-525_-523delCCT		5_prime_UTR_variant	1/11	1		ENSP00000396219.2
MEF2C	ENST00000340208.9	c.-143+4162_-143+4164delCCT		intron_variant		1		ENSP00000340874.5
MEF2C	ENST00000424173.6	c.-143+4162_-143+4164delCCT		intron_variant		1		ENSP00000389610.2

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 381 AN: 150060 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00243

GnomAD4 exome AF: 0.0122 AC: 17 AN: 1392 Hom.: 0 AF XY: 0.0134 AC XY: 12 AN XY: 896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00568

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00253 AC: 380 AN: 150158 Hom.: 3 Cov.: 27 AF XY: 0.00308 AC XY: 226 AN XY: 73392

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00127

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.00211

Gnomad4 OTH AF: 0.00241

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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: rs567979916; hg19: chr5-88179154;