18-54204978-C-T

Variant names:

• chr18-54204978-C-T
• rs16957946
• NM_003927.5:c.702+20G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003927.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD2	NM_003927.5	MANE Select	c.702+20G>A		intron	N/A	NP_003918.1
	MBD2	NM_015832.6		c.702+20G>A		intron	N/A	NP_056647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD2	ENST00000256429.8	TSL:1 MANE Select	c.702+20G>A		intron	N/A	ENSP00000256429.3
	MBD2	ENST00000583046.1	TSL:1	c.702+20G>A		intron	N/A	ENSP00000464554.1
	MBD2	ENST00000398398.6	TSL:2	c.702+20G>A		intron	N/A	ENSP00000381435.2

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

GnomAD2 exomes AF: 0.0237 AC: 5846 AN: 246956 AF XY: 0.0246

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 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

African (AFR) AF: 0.00148 AC: 49 AN: 33202

American (AMR) AF: 0.00119 AC: 52 AN: 43742

Ashkenazi Jewish (ASJ) AF: 0.00668 AC: 173 AN: 25914

East Asian (EAS) AF: 0.144 AC: 5700 AN: 39580

South Asian (SAS) AF: 0.0425 AC: 3616 AN: 85076

European-Finnish (FIN) AF: 0.0313 AC: 1665 AN: 53222

Middle Eastern (MID) AF: 0.00977 AC: 56 AN: 5734

European-Non Finnish (NFE) AF: 0.00625 AC: 6926 AN: 1108620

Other (OTH) AF: 0.0157 AC: 944 AN: 60168

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

African (AFR) AF: 0.00294 AC: 122 AN: 41542

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.141 AC: 730 AN: 5184

South Asian (SAS) AF: 0.0460 AC: 222 AN: 4828

European-Finnish (FIN) AF: 0.0325 AC: 344 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00679 AC: 462 AN: 68018

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.70
DANN	Benign	0.59
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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