rs1554098567

Positions:

• chr5-88722695-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_002397.5(MEF2C):​c.1331A>C​(p.His444Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEF2C NM_002397.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.65

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEF2C. . Gene score misZ 3.9523 (greater than the threshold 3.09). Trascript score misZ 4.8218 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 20, complex neurodevelopmental disorder.
• BP6: Variant 5-88722695-T-G is Benign according to our data. Variant chr5-88722695-T-G is described in ClinVar as [Benign]. Clinvar id is 471459.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2C	NM_002397.5	c.1331A>C	p.His444Pro	missense_variant	11/11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7	c.1331A>C	p.His444Pro	missense_variant	11/11	1	NM_002397.5	ENSP00000421925.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.;.;T;.;.;T;T;.;T;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;.;D;.;D;.;D;.;D;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;M;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.4	D;D;D;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.018	D;D;D;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Benign	0.22	T;T;T;.;.;T;T;T;T;T;.;T;T;.;T;T;.;T;T
Polyphen		1.0	D;.;.;.;.;.;D;.;.;.;.;.;P;D;.;P;.;.;.
Vest4		0.59
MutPred		0.13		Gain of relative solvent accessibility (P = 0.0479);.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0479);.;.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0479);.;.;.;.;.;
MVP		0.90
MPC		3.2
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.61

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: rs1554098567; hg19: chr5-88018512;