rs797045703

Positions:

chr5-88728572-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The ENST00000504921.7(MEF2C):c.1021G>A(p.Ala341Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000507 in 1,380,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

MEF2C
ENST00000504921.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.15200692).

BP6

Variant 5-88728572-C-T is Benign according to our data. Variant chr5-88728572-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211492.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEF2C	NM_002397.5 linkuse as main transcript	c.1021G>A	p.Ala341Thr	missense_variant	10/11	ENST00000504921.7	NP_002388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921.7 linkuse as main transcript	c.1021G>A	p.Ala341Thr	missense_variant	10/11	1	NM_002397.5	ENSP00000421925		Q06413-1
MEF2C-AS2	ENST00000657578.1 linkuse as main transcript	n.232-33425C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000651

AC:

AN:

153582

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000507

AC:

AN:

1380488

Hom.:

Cov.:

AF XY:

0.00000735

AC XY:

AN XY:

680350

show subpopulations

Gnomad4 AFR exome

AF:

0.0000322

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000468

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

MEF2C: PM2, PP2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 20, 2015

- -

Intellectual disability, autosomal dominant 20

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.086

T;.;.;T;.;.;T;T;.;T;.;.;.;.;T;T;.;.;.;.;.;.

Eigen

Benign

-0.053

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.;.;N;.;N;.;N;.;.;N;N;.;N;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.71

N;N;N;.;.;.;N;.;N;N;N;.;N;.;.;.;N;.;.;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.47

T;T;T;.;.;.;T;.;T;T;T;.;T;.;.;.;T;.;.;.;.;.

Sift4G

Benign

0.64

T;T;T;.;.;T;T;T;T;T;T;.;T;T;.;T;T;T;T;.;T;T

Polyphen

0.0060

B;.;.;.;.;.;B;.;.;.;.;.;.;P;B;.;P;.;.;.;.;.

Vest4

0.24

MutPred

0.23

Gain of disorder (P = 0.1115);.;.;.;Gain of disorder (P = 0.1115);.;Gain of disorder (P = 0.1115);.;Gain of disorder (P = 0.1115);.;Gain of disorder (P = 0.1115);Gain of disorder (P = 0.1115);Gain of disorder (P = 0.1115);.;Gain of disorder (P = 0.1115);.;.;.;.;.;.;.;

MVP

0.49

MPC

1.3

ClinPred

0.40

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.088

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over