Genetic Variant MEF2C:p.Asn214Lys (chr5-88731897-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002397.5(MEF2C):c.642C>G(p.Asn214Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,182 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N214N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MEF2C
NM_002397.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.185

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002397.5. 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.642C>G	p.Asn214Lys	missense	Exon 7 of 11	NP_002388.2
MEF2C	NM_001193347.1		c.696C>G	p.Asn232Lys	missense	Exon 9 of 12	NP_001180276.1
MEF2C	NM_001193350.2		c.642C>G	p.Asn214Lys	missense	Exon 7 of 11	NP_001180279.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.642C>G	p.Asn214Lys	missense	Exon 7 of 11	ENSP00000421925.5
MEF2C	ENST00000340208.9	TSL:1	c.696C>G	p.Asn232Lys	missense	Exon 9 of 12	ENSP00000340874.5
MEF2C	ENST00000437473.6	TSL:1	c.642C>G	p.Asn214Lys	missense	Exon 7 of 11	ENSP00000396219.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454182

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33184

American (AMR)

AF:

0.00

AC:

AN:

43870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39562

South Asian (SAS)

AF:

0.00

AC:

AN:

85270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107428

Other (OTH)

AF:

0.00

AC:

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Benign

0.13

Eigen_PC

Benign

0.015

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.0

PhyloP100

0.18

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.88

MutPred

0.25

Gain of ubiquitination at N214 (P = 0.0094)

MVP

0.91

MPC

2.0

ClinPred

1.0

GERP RS

-3.8

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.78

gMVP

0.90

Mutation Taster

=9/91

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over