18-54224432-G-A

Position:

chr18-54224432-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000256429.8(MBD2):c.128C>T(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,240,086 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P43Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 9.2e-7 ( 0 hom. )

Consequence

MBD2
ENST00000256429.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24424165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD2	NM_003927.5 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	1/7	ENST00000256429.8	NP_003918.1
MBD2	NM_015832.6 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	1/3		NP_056647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD2	ENST00000256429.8 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	1/7	1	NM_003927.5	ENSP00000256429	P1	Q9UBB5-1
MBD2	ENST00000583046.1 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	1/3	1		ENSP00000464554		Q9UBB5-3
MBD2	ENST00000398398.6 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	1/3	2		ENSP00000381435

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.000492

GnomAD4 exome

AF:

9.17e-7

AC:

AN:

1090680

Hom.:

Cov.:

AF XY:

0.00000192

AC XY:

AN XY:

521836

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:

0.00000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149406

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72896

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000149

Gnomad4 OTH

AF:

0.000492

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 09, 2023

The c.128C>T (p.P43L) 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 128, causing the proline (P) at amino acid position 43 to be replaced by a leucine (L). 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

Benign

0.18

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.68

T;T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

0.0

N;.;N

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.40

N;N;.

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D;.

Sift4G

Benign

0.33

T;T;D

Polyphen

0.26

B;.;P

Vest4

0.18

MutPred

0.30

Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);

MVP

0.40

MPC

1.8

ClinPred

0.44

GERP RS

1.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

4.6

Varity_R

0.14

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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