chr5-88823787-A-T

Variant names:

• chr5-88823787-A-T
• rs545185248
• NM_002397.5:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_002397.5(MEF2C):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEF2C NM_002397.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 25 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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 12 codons. Genomic position: 88823755. Lost 0.024 part of the original CDS.
• PS1: Another start lost variant in NM_002397.5 (MEF2C) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	NM_002397.5	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 2 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.2T>A	p.Met1?	start_lost	Exon 3 of 12	NP_001180276.1
	MEF2C	NM_001193350.2		c.2T>A	p.Met1?	start_lost	Exon 2 of 11	NP_001180279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 2 of 11	ENSP00000421925.5
	MEF2C	ENST00000340208.9	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 3 of 12	ENSP00000340874.5
	MEF2C	ENST00000437473.6	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 2 of 11	ENSP00000396219.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		8.9
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.87
MutPred		0.77		Loss of stability (P = 0.0397)
MVP		0.99
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.028	Neutral
Varity_R		0.94
gMVP		0.99
Mutation Taster		=2/198	disease causing

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: rs545185248; hg19: chr5-88119604;