19-19146309-C-T

Variant names:

• chr19-19146309-C-T
• rs2146349593
• NM_001145785.2:c.845G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145785.2(MEF2B):​c.845G>A​(p.Arg282Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,193,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MEF2B NM_001145785.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.917
• Publications: 0 publications found

Genes affected

MEF2B (HGNC:6995): (myocyte enhancer factor 2B) The product of this gene is a member of the MADS/MEF2 family of DNA binding proteins. The protein is thought to regulate gene expression, including expression of the smooth muscle myosin heavy chain gene. This region undergoes considerable alternative splicing, with transcripts supporting two non-overlapping loci (GeneID 729991 and 100271849) as well as numerous read-through transcripts that span both loci (annotated as GeneID 4207). Several isoforms of this protein are expressed from either this locus or from some of the read-through transcripts annotated on GeneID 4207. [provided by RefSeq, Jan 2014]

BORCS8-MEF2B (HGNC:39979): (BORCS8-MEF2B readthrough) This gene represents numerous read-through transcripts that span GeneID:729991 and 100271849. Many read-through transcripts are predicted to be nonsense-mediated decay (NMD) candidates, and are thought to be non-coding. Some transcripts are predicted to be capable of translation reinitiation at a downstream AUG, resulting in expression of at least one isoform of myocyte enhancer factor 2B (MEF2B) from this read-through locus. At least one additional MEF2B variant and isoform can be expressed from a downstream promoter, and is annotated on GeneID:100271849. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1093466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEF2B	NM_001145785.2	c.845G>A	p.Arg282Lys	missense_variant	Exon 8 of 9	ENST00000424583.7	NP_001139257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEF2B	ENST00000424583.7	c.845G>A	p.Arg282Lys	missense_variant	Exon 8 of 9	5	NM_001145785.2	ENSP00000402154.2
BORCS8-MEF2B	ENST00000514819.7	c.820+246G>A		intron_variant	Intron 8 of 8	5		ENSP00000454967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000117 AC: 14 AN: 1193074 Hom.: 0 Cov.: 22 AF XY: 0.0000104 AC XY: 6 AN XY: 575120

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24508

American (AMR) AF: 0.00 AC: 0 AN: 12624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17310

East Asian (EAS) AF: 0.00 AC: 0 AN: 29178

South Asian (SAS) AF: 0.0000198 AC: 1 AN: 50418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.0000133 AC: 13 AN: 975660

Other (OTH) AF: 0.00 AC: 0 AN: 49804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>A (p.R282K) alteration is located in exon 8 (coding exon 7) of the MEF2B gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.00074	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.63	T
PhyloP100		0.92
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.68	T;T;T
Polyphen		0.024	B;.;B
Vest4		0.084
MutPred		0.33		.;.;Gain of solvent accessibility (P = 0.0022);
MVP		0.25
ClinPred		0.15	T
GERP RS		3.4
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2146349593; hg19: chr19-19257118;