18-54224367-T-C

Position:

• chr18-54224367-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000256429.8(MBD2):​c.193A>G​(p.Lys65Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,048,998 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: MBD2 ENST00000256429.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.131

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]

ACMG classification

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=0.22339523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD2	NM_003927.5	c.193A>G	p.Lys65Glu	missense_variant	1/7	ENST00000256429.8	NP_003918.1
MBD2	NM_015832.6	c.193A>G	p.Lys65Glu	missense_variant	1/3		NP_056647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD2	ENST00000256429.8	c.193A>G	p.Lys65Glu	missense_variant	1/7	1	NM_003927.5	ENSP00000256429	P1
MBD2	ENST00000583046.1	c.193A>G	p.Lys65Glu	missense_variant	1/3	1		ENSP00000464554
MBD2	ENST00000398398.6	c.193A>G	p.Lys65Glu	missense_variant	1/3	2		ENSP00000381435

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000381 AC: 4 AN: 1048998 Hom.: 0 Cov.: 29 AF XY: 0.00000198 AC XY: 1 AN XY: 503824

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: 0.00000446

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 06, 2023

The c.193A>G (p.K65E) alteration is located in exon 1 (coding exon 1) of the MBD2 gene. This alteration results from a A to G substitution at nucleotide position 193, causing the lysine (K) at amino acid position 65 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.13	N;N;.
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.16
MutPred		0.26		Loss of methylation at K65 (P = 0.0069);Loss of methylation at K65 (P = 0.0069);Loss of methylation at K65 (P = 0.0069);
MVP		0.66
MPC		2.3
ClinPred		0.25	T
GERP RS		1.7
Varity_R		0.29
gMVP		0.077

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-51750737;