5-88720336-ATTTT-ATTT

Variant names:

• chr5-88720336-AT-A
• rs3841444
• ENST00000437473.6:c.*2267delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000437473.6(MEF2C):​c.*2267delA variant causes a splice region change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (0 hom.)
• Consequence: MEF2C ENST00000437473.6 splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00700
• Publications: 3 publications found

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

ACMG classification

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

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00239 (356/149240) while in subpopulation NFE AF = 0.00296 (199/67136). AF 95% confidence interval is 0.00263. There are 0 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 356 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000437473.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	NM_002397.5	MANE Select	c.*2267delA		3_prime_UTR	Exon 11 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.*2267delA		3_prime_UTR	Exon 12 of 12	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.*2267delA		3_prime_UTR	Exon 11 of 11	NP_001180279.1	Q06413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2C	ENST00000437473.6	TSL:1	c.*2267delA		splice_region	Exon 11 of 11	ENSP00000396219.2	Q06413-1
	MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.*2267delA		3_prime_UTR	Exon 11 of 11	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.*2267delA		3_prime_UTR	Exon 12 of 12	ENSP00000340874.5	Q06413-5

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 356 AN: 149134 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00261

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.000921

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00296

Gnomad OTH AF: 0.00439

GnomAD4 exome AF: 0.00278 AC: 1 AN: 360 Hom.: 0 Cov.: 0 AF XY: 0.00450 AC XY: 1 AN XY: 222

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00282 AC: 1 AN: 354

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00239 AC: 356 AN: 149240 Hom.: 0 Cov.: 0 AF XY: 0.00239 AC XY: 174 AN XY: 72716

African (AFR) AF: 0.00211 AC: 86 AN: 40810

American (AMR) AF: 0.00260 AC: 39 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 5 AN: 3432

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.00148 AC: 7 AN: 4740

European-Finnish (FIN) AF: 0.000921 AC: 9 AN: 9776

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00296 AC: 199 AN: 67136

Other (OTH) AF: 0.00435 AC: 9 AN: 2070

Alfa AF: 0.00299 Hom.: 1128

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual Disability, Stereotypic Movements, Epilepsy, and/or Cerebral Malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0070
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

Other links and lift over

dbSNP: rs3841444; hg19: chr5-88016153;