dbSNP rs587783747: MEF2C:p.Arg189* (chr5-88751881-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001193347.1(MEF2C):c.619C>T(p.Arg207*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R207R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

MEF2C
NM_001193347.1 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.86

Publications

9 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 links:

MEF2C-AS2 (HGNC:53115): (MEF2C antisense RNA 2)

MEF2C-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-88751881-G-A is Pathogenic according to our data. Variant chr5-88751881-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193347.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MEF2C	NM_002397.5	MANE Select	c.565C>T	p.Arg189*	stop_gained	Exon 5 of 11	NP_002388.2
MEF2C	NM_001193347.1		c.619C>T	p.Arg207*	stop_gained	Exon 7 of 12	NP_001180276.1
MEF2C	NM_001193350.2		c.565C>T	p.Arg189*	stop_gained	Exon 5 of 11	NP_001180279.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.565C>T	p.Arg189*	stop_gained	Exon 5 of 11	ENSP00000421925.5
MEF2C	ENST00000340208.9	TSL:1	c.619C>T	p.Arg207*	stop_gained	Exon 7 of 12	ENSP00000340874.5
MEF2C	ENST00000437473.6	TSL:1	c.565C>T	p.Arg189*	stop_gained	Exon 5 of 11	ENSP00000396219.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (6)

Inborn genetic diseases (1)

MEF2C-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.93

PhyloP100

4.9

Vest4

0.89

GERP RS

4.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over