rs16957946

Positions:

• chr18-54204978-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003927.5(MBD2):​c.702+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,607,522 control chromosomes in the GnomAD database, including 652 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (62 hom., cov: 31)
  • Exomes 𝑓: 0.013 (590 hom.)
• Consequence: MBD2 NM_003927.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD2	NM_003927.5	c.702+20G>A		intron_variant		ENST00000256429.8	NP_003918.1
MBD2	NM_015832.6	c.702+20G>A		intron_variant			NP_056647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD2	ENST00000256429.8	c.702+20G>A		intron_variant		1	NM_003927.5	ENSP00000256429	P1
MBD2	ENST00000583046.1	c.702+20G>A		intron_variant		1		ENSP00000464554
MBD2	ENST00000398398.6	c.702+20G>A		intron_variant		2		ENSP00000381435
MBD2	ENST00000578272.1	c.24+20G>A		intron_variant, NMD_transcript_variant		5		ENSP00000462393

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1948 AN: 152146 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00676

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0237 AC: 5846 AN: 246956 Hom.: 271 AF XY: 0.0246 AC XY: 3280 AN XY: 133498

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00741

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.0424

Gnomad FIN exome AF: 0.0334

Gnomad NFE exome AF: 0.00792

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0132 AC: 19181 AN: 1455258 Hom.: 590 Cov.: 30 AF XY: 0.0141 AC XY: 10231 AN XY: 723778

Gnomad4 AFR exome AF: 0.00148

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00668

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.0425

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.00625

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152264 Hom.: 62 Cov.: 31 AF XY: 0.0152 AC XY: 1133 AN XY: 74442

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.0460

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.00679

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00854 Hom.: 1

Bravo AF: 0.0101

Asia WGS AF: 0.0680 AC: 236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.70
DANN	Benign	0.59

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: rs16957946; hg19: chr18-51731348; COSMIC: COSV56503812;