dbSNP rs587783749: MEF2C:p.Leu278fs (chr5-88730211-CA-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.95

Publications

3 publications found

Variant links:

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 links:

MEF2C-AS2 (HGNC:53115): (MEF2C antisense RNA 2)

MEF2C-AS2 links:

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ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEF2C	NM_002397.5	MANE Select	c.833delT	p.Leu278fs	frameshift splice_region	Exon 8 of 11	NP_002388.2
MEF2C	NM_001193350.2		c.833delT	p.Leu278fs	frameshift splice_region	Exon 8 of 11	NP_001180279.1	Q06413-1
MEF2C	NM_001364329.2		c.833delT	p.Leu278fs	frameshift splice_region	Exon 9 of 12	NP_001351258.1	Q06413-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.833delT	p.Leu278fs	frameshift splice_region	Exon 8 of 11	ENSP00000421925.5	Q06413-1
MEF2C	ENST00000437473.6	TSL:1	c.833delT	p.Leu278fs	frameshift splice_region	Exon 8 of 11	ENSP00000396219.2	Q06413-1
MEF2C	ENST00000626391.2	TSL:1	c.689delT	p.Leu230fs	frameshift splice_region	Exon 6 of 9	ENSP00000487184.1	D8L7E9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431448

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708856

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32888

American (AMR)

AF:

0.00

AC:

AN:

40538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25562

East Asian (EAS)

AF:

0.00

AC:

AN:

38448

South Asian (SAS)

AF:

0.00

AC:

AN:

81504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095716

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.9

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over