5-88720336-ATTTT-ATTTTTT

Variant names:

• chr5-88720336-A-ATT
• rs3841444
• ENST00000437473.6:c.*2266_*2267dupAA

Variant summary

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

The ENST00000437473.6(MEF2C):​c.*2266_*2267dupAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.025 (59 hom., cov: 0)
  • Exomes 𝑓: 0.014 (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 afr. GnomAd4 allele frequency = 0.0249 (3719/149228) while in subpopulation AFR AF = 0.0422 (1723/40816). AF 95% confidence interval is 0.0406. There are 59 homozygotes in GnomAd4. There are 1729 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 3719 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.*2266_*2267dupAA		3_prime_UTR	Exon 11 of 11	NP_002388.2
	MEF2C	NM_001193347.1		c.*2266_*2267dupAA		3_prime_UTR	Exon 12 of 12	NP_001180276.1	Q06413-5
	MEF2C	NM_001193350.2		c.*2266_*2267dupAA		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.*2266_*2267dupAA		splice_region	Exon 11 of 11	ENSP00000396219.2	Q06413-1
	MEF2C	ENST00000504921.7	TSL:1 MANE Select	c.*2266_*2267dupAA		3_prime_UTR	Exon 11 of 11	ENSP00000421925.5	Q06413-1
	MEF2C	ENST00000340208.9	TSL:1	c.*2266_*2267dupAA		3_prime_UTR	Exon 12 of 12	ENSP00000340874.5	Q06413-5

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3710 AN: 149124 Hom.: 59 Cov.: 0

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00350

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.00973

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.0137 AC: 5 AN: 364 Hom.: 0 Cov.: 0 AF XY: 0.0223 AC XY: 5 AN XY: 224

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: 0.0140 AC: 5 AN: 358

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: 0.0249 AC: 3719 AN: 149228 Hom.: 59 Cov.: 0 AF XY: 0.0238 AC XY: 1729 AN XY: 72714

African (AFR) AF: 0.0422 AC: 1723 AN: 40816

American (AMR) AF: 0.0164 AC: 246 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.00350 AC: 12 AN: 3432

East Asian (EAS) AF: 0.00118 AC: 6 AN: 5106

South Asian (SAS) AF: 0.0414 AC: 196 AN: 4740

European-Finnish (FIN) AF: 0.00973 AC: 95 AN: 9762

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.0207 AC: 1393 AN: 67138

Other (OTH) AF: 0.0213 AC: 44 AN: 2070

Alfa AF: 0.0102 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3841444; hg19: chr5-88016153;