Genetic Variant MEF2C:c.*31_*32delTT (chr5-88722571-GAA-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_002397.5(MEF2C):c.*31_*32delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,316,828 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0043 ( 7 hom., cov: 28)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

MEF2C
NM_002397.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00429 (598/139378) while in subpopulation AFR AF = 0.014 (542/38684). AF 95% confidence interval is 0.013. There are 7 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 598 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2C	NM_002397.5 link	c.31_32delTT		3_prime_UTR_variant	Exon 11 of 11	ENST00000504921.7	NP_002388.2	Q06413-1A0A024RAL7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2C	ENST00000504921 link	c.31_32delTT		3_prime_UTR_variant	Exon 11 of 11	1	NM_002397.5	ENSP00000421925.5		Q06413-1

Frequencies

GnomAD3 genomes

AF:

0.00429

AC:

598

AN:

139346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00245

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:

0.000252

Gnomad OTH

AF:

0.00315

GnomAD2 exomes

AF:

0.00413

AC:

426

AN:

103102

AF XY:

0.00331

show subpopulations

Gnomad AFR exome

AF:

0.0252

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00279

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00301

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00286

GnomAD4 exome

AF:

0.00105

AC:

1234

AN:

1177450

Hom.:

AF XY:

0.00102

AC XY:

599

AN XY:

586270

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

AC:

502

AN:

27502

Gnomad4 AMR exome

AF:

0.00130

AC:

AN:

34598

Gnomad4 ASJ exome

AF:

0.000476

AC:

AN:

21010

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

34454

Gnomad4 SAS exome

AF:

0.000380

AC:

AN:

71104

Gnomad4 FIN exome

AF:

0.00150

AC:

AN:

43446

Gnomad4 NFE exome

AF:

0.000581

AC:

518

AN:

891346

Gnomad4 Remaining exome

AF:

0.00122

AC:

AN:

49362

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00429

AC:

598

AN:

139378

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

284

AN XY:

67260

show subpopulations

Gnomad4 AFR

AF:

0.0140

AC:

0.014011

AN:

0.014011

Gnomad4 AMR

AF:

0.00245

AC:

0.00244851

AN:

0.00244851

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000252

AC:

0.000252406

AN:

0.000252406

Gnomad4 OTH

AF:

0.00313

AC:

0.00313152

AN:

0.00313152

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual Disability, Stereotypic Movements, Epilepsy, and/or Cerebral Malformations

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

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