rs587783749

Variant names:

• chr5-88730211-CA-C
• rs587783749
• NM_002397.5:c.833delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002397.5(MEF2C):​c.833delT​(p.Leu278fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,448 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MEF2C NM_002397.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.95
• Publications: 3 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-88730211-CA-C is Pathogenic according to our data. Variant chr5-88730211-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 158888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.833delT	p.Leu278fs	frameshift_variant, splice_region_variant	Exon 8 of 11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.833delT	p.Leu278fs	frameshift_variant, splice_region_variant	Exon 8 of 11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431448 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708856

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

African (AFR) AF: 0.00 AC: 0 AN: 32888

American (AMR) AF: 0.00 AC: 0 AN: 40538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25562

East Asian (EAS) AF: 0.00 AC: 0 AN: 38448

South Asian (SAS) AF: 0.00 AC: 0 AN: 81504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095716

Other (OTH) AF: 0.00 AC: 0 AN: 59328

⚠️ 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 Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language Pathogenic:2

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Jun 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.833delT (p.L278*) alteration, located in exon 8 (coding exon 7) of the MEF2C gene, consists of a deletion of one nucleotide at position 833. This changes the amino acid from a leucine (L) to a stop codon at amino acid position 278. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in two individuals with features consistent with MEF2C-related neurodevelopmental disorder, including a de novo occurrence (Paciorkowski, 2013; Yan, 2023). Based on the available evidence, this alteration is classified as pathogenic.

not provided Pathogenic:1

May 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in an individual with global delays, epilepsy, hyperkinesis, and normal brain MRI in the literature (Paciorkowski et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23389741)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587783749; hg19: chr5-88026028;