rs545185248

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_002397.5(MEF2C):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MEF2C
NM_002397.5 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.87

Publications

25 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 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

MEF2C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 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;

PP5

Variant 5-88823787-A-G is Pathogenic according to our data. Variant chr5-88823787-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 211494.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 link	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENST00000504921.7	NP_002388.2	Q06413-1A0A024RAL7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7 link	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	1	NM_002397.5	ENSP00000421925.5		Q06413-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248516

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74254

show subpopulations

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

African (AFR)

AF:

0.0000241

AC:

AN:

41520

American (AMR)

AF:

0.00

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67880

Other (OTH)

AF:

0.00

AC:

AN:

2100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

Pathogenic:2

Jan 09, 2015

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2023

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEF2C c.2T>C (p.Met1?) variant alters the initiator methionine amino acid and the resultant protein is described as p.Met1? to denote that whether the loss of the methionine at codon 1 prevents all protein translation or causes abnormal protein formation from an alternate methionine is unknown. To our knowledge, this variant has not been reported in the peer-reviewed literature. However, three different start loss variants, including at least two de novo variants, have been reported in individuals with MEF2C deficiency (PMID: 34055696; 26633542). The c.2T>C variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000065 in the African/ African American population (version 2.1.1). This variant was identified in a de novo state. Based on the available evidence, the c.2T>C (p.Met1?) variant is classified as likely pathogenic for neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language. -

not provided

Pathogenic:1

Aug 28, 2018

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The de novo c.2T>C pathogenic variant in the MEF2C gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. As this pathogenic variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. We interpret c.2T>C as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.;.;T;.;.;D;T;.;T;.;.;.;.;D;T;.;.;.;.;.;T;T;.;.;T;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;.;D;.;D;.;D;.;D;D;.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

PhyloP100

8.9

PROVEAN

Pathogenic

-5.1

D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;D;D;.;D;D;D;D;.;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;.;.;.;D;.;D;D;D;.;D;.;.;.;D;.;.;D;D;.;D;D;D;D;.;D;.

Sift4G

Pathogenic

0.0010

D;D;D;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.;D;D;.;.;D;D;.;.;.

Polyphen

0.91

P;.;.;.;.;.;P;.;.;.;.;.;.;D;P;.;D;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.89

MutPred

0.76

Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);Gain of phosphorylation at M1 (P = 0.0073);

MVP

0.98

ClinPred

1.0

GERP RS

5.1

PromoterAI

0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.96

Mutation Taster

=2/198

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over