Genetic Variant MEF2B:p.Gly261Arg (chr19-19146373-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001145785.2(MEF2B):c.781G>A(p.Gly261Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MEF2B
NM_001145785.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.538

Publications

0 publications found

Variant links:

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]

MEF2B links:

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]

BORCS8-MEF2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3199538).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEF2B	NM_001145785.2	MANE Select	c.781G>A	p.Gly261Arg	missense	Exon 8 of 9	NP_001139257.1	Q02080-2
MEF2B	NM_001367282.1		c.769+182G>A		intron	N/A	NP_001354211.1	Q02080-1
BORCS8-MEF2B	NM_005919.4		c.769+182G>A		intron	N/A	NP_005910.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEF2B	ENST00000424583.7	TSL:5 MANE Select	c.781G>A	p.Gly261Arg	missense	Exon 8 of 9	ENSP00000402154.2	Q02080-2
BORCS8-MEF2B	ENST00000514819.7	TSL:5	c.820+182G>A		intron	N/A	ENSP00000454967.3	H3BNR1
MEF2B	ENST00000410050.5	TSL:5	c.802G>A	p.Gly268Arg	missense	Exon 8 of 9	ENSP00000386374.1	C9J4J4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

976732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

478772

African (AFR)

AF:

0.00

AC:

AN:

20556

American (AMR)

AF:

0.00

AC:

AN:

13026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16088

East Asian (EAS)

AF:

0.00

AC:

AN:

28514

South Asian (SAS)

AF:

0.00

AC:

AN:

48718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4554

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

771726

Other (OTH)

AF:

0.00

AC:

AN:

42592

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.037

Eigen

Benign

0.18

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.32

MetaSVM

Uncertain

-0.066

PhyloP100

0.54

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.35

Sift

Uncertain

0.0060

Sift4G

Benign

0.73

Polyphen

0.98

Vest4

0.38

MutPred

0.25

Gain of solvent accessibility (P = 0.0037)

MVP

0.14

ClinPred

0.81

GERP RS

4.4

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over