18-54159821-T-C

Position:

• chr18-54159821-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003927.5(MBD2):​c.1192A>G​(p.Thr398Ala) 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. 13/21 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)
• Consequence: MBD2 NM_003927.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.980

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054162085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD2	NM_003927.5	c.1192A>G	p.Thr398Ala	missense_variant	6/7	ENST00000256429.8	NP_003918.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD2	ENST00000256429.8	c.1192A>G	p.Thr398Ala	missense_variant	6/7	1	NM_003927.5	ENSP00000256429.3
MBD2	ENST00000578272.1	n.*419A>G		non_coding_transcript_exon_variant	6/6	5		ENSP00000462393.1
MBD2	ENST00000579025.1	n.127A>G		non_coding_transcript_exon_variant	2/3	3
MBD2	ENST00000578272.1	n.*419A>G		3_prime_UTR_variant	6/6	5		ENSP00000462393.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2023

The c.1192A>G (p.T398A) alteration is located in exon 6 (coding exon 6) of the MBD2 gene. This alteration results from a A to G substitution at nucleotide position 1192, causing the threonine (T) at amino acid position 398 to be replaced by an alanine (A). 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	0.071
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.054	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	-0.55	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.023	D
Sift4G	Benign	0.70	T
Polyphen		0.0080	B
Vest4		0.053
MutPred		0.14		Gain of helix (P = 0.0082);
MVP		0.66
MPC		0.53
ClinPred		0.31	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.44

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

Other links and lift over

dbSNP: rs1568077184; hg19: chr18-51686191;