Variant 18-54224280-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003927.5(MBD2):c.280C>T(p.Arg94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 929,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MBD2
NM_003927.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.185

Variant links:

Genes affected

MBD2 (HGNC:6917): (methyl-CpG binding domain protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. The protein encoded by this gene may function as a mediator of the biological consequences of the methylation signal. It is also reported that the this protein functions as a demethylase to activate transcription, as DNA methylation causes gene silencing. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

MBD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2748693).

BS2

High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD2	NM_003927.5 linkuse as main transcript	c.280C>T	p.Arg94Cys	missense_variant	1/7	ENST00000256429.8	NP_003918.1	Q9UBB5-1
MBD2	NM_015832.6 linkuse as main transcript	c.280C>T	p.Arg94Cys	missense_variant	1/3		NP_056647.1	Q9UBB5-3A0A024R2B8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MBD2	ENST00000256429.8 linkuse as main transcript	c.280C>T	p.Arg94Cys	missense_variant	1/7	1	NM_003927.5	ENSP00000256429.3	Q9UBB5-1
MBD2	ENST00000583046.1 linkuse as main transcript	c.280C>T	p.Arg94Cys	missense_variant	1/3	1		ENSP00000464554.1	Q9UBB5-3
MBD2	ENST00000398398.6 linkuse as main transcript	c.280C>T	p.Arg94Cys	missense_variant	1/3	2		ENSP00000381435.2	X6RBL6

Frequencies

GnomAD3 genomes

AF:

0.0000140

AC:

AN:

143294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000509

AC:

AN:

785930

Hom.:

Cov.:

AF XY:

0.0000357

AC XY:

AN XY:

364342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000530

Gnomad4 OTH exome

AF:

0.0000774

GnomAD4 genome

AF:

0.0000140

AC:

AN:

143294

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

69666

show subpopulations

Gnomad4 AFR

AF:

0.0000502

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The c.280C>T (p.R94C) alteration is located in exon 1 (coding exon 1) of the MBD2 gene. This alteration results from a C to T substitution at nucleotide position 280, causing the arginine (R) at amino acid position 94 to be replaced by a cysteine (C). 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

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Benign

0.88

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.70

T;T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

0.0

N;.;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.43

N;N;.

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.052

T;T;T

Polyphen

0.98

D;.;D

Vest4

0.23

MutPred

0.42

Loss of methylation at R94 (P = 0.0012);Loss of methylation at R94 (P = 0.0012);Loss of methylation at R94 (P = 0.0012);

MVP

0.61

MPC

2.2

ClinPred

0.36

GERP RS

2.5

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.5

Varity_R

0.24

gMVP

0.22

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over