chr5-88804776-C-G

Variant names:

• chr5-88804776-C-G
• rs397514656
• NM_002397.5:c.80G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_002397.5(MEF2C):​c.80G>C​(p.Gly27Ala) variant causes a missense 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G27R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91
• 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 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_002397.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-88804777-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2169514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 5-88804776-C-G is Pathogenic according to our data. Variant chr5-88804776-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40216.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	NM_002397.5	MANE Select	c.80G>C	p.Gly27Ala	missense	Exon 3 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.80G>C	p.Gly27Ala	missense	Exon 4 of 12	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.80G>C	p.Gly27Ala	missense	Exon 3 of 11	NP_001180279.1	Q06413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.80G>C	p.Gly27Ala	missense	Exon 3 of 11	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.80G>C	p.Gly27Ala	missense	Exon 4 of 12	ENSP00000340874.5	Q06413-5
	MEF2C	ENST00000437473.6	TSL:1	c.80G>C	p.Gly27Ala	missense	Exon 3 of 11	ENSP00000396219.2	Q06413-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.92		Gain of helix (P = 0.062)
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	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: rs397514656; hg19: chr5-88100593;