chr19-19149293-C-A

Variant names:

• chr19-19149293-C-A
• rs371035718
• NM_001145785.2:c.191G>T

Variant summary

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

The NM_001145785.2(MEF2B):​c.191G>T​(p.Arg64Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R64H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEF2B NM_001145785.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.91
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145785.2. 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
	MEF2B	NM_001145785.2	MANE Select	c.191G>T	p.Arg64Leu	missense	Exon 3 of 9	NP_001139257.1	Q02080-2
	MEF2B	NM_001367282.1		c.191G>T	p.Arg64Leu	missense	Exon 3 of 8	NP_001354211.1	Q02080-1
	BORCS8-MEF2B	NM_005919.4		c.191G>T	p.Arg64Leu	missense	Exon 5 of 10	NP_005910.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEF2B	ENST00000424583.7	TSL:5 MANE Select	c.191G>T	p.Arg64Leu	missense	Exon 3 of 9	ENSP00000402154.2	Q02080-2
	BORCS8-MEF2B	ENST00000514819.7	TSL:5	c.242G>T	p.Arg81Leu	missense	Exon 4 of 9	ENSP00000454967.3	H3BNR1
	MEF2B	ENST00000410050.5	TSL:5	c.191G>T	p.Arg64Leu	missense	Exon 3 of 9	ENSP00000386374.1	C9J4J4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.93	P
Vest4		0.60
MutPred		0.33		Gain of ubiquitination at K68 (P = 0.086)
MVP		0.80
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.61
Mutation Taster		=29/71	disease causing

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: rs371035718; hg19: chr19-19260102;