rs2044760

Variant names:

• chr2-148232162-T-C
• rs2044760
• NM_001378120.1:c.-830-1083T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378120.1(MBD5):​c.-830-1083T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 151,990 control chromosomes in the GnomAD database, including 27,747 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 0.60 (27747 hom., cov: 33)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.236
• Publications: 4 publications found

Genes affected

MBD5 (HGNC:20444): (methyl-CpG binding domain protein 5) This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

MBD5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-830-1083T>C		intron_variant	Intron 2 of 13	ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-830-1083T>C		intron_variant	Intron 2 of 13		NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91447 AN: 151872 Hom.: 27738 Cov.: 33

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.615

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.602 AC: 91489 AN: 151990 Hom.: 27747 Cov.: 33 AF XY: 0.601 AC XY: 44682 AN XY: 74294

African (AFR) AF: 0.515 AC: 21356 AN: 41442

American (AMR) AF: 0.587 AC: 8971 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2226 AN: 3466

East Asian (EAS) AF: 0.721 AC: 3730 AN: 5172

South Asian (SAS) AF: 0.567 AC: 2731 AN: 4820

European-Finnish (FIN) AF: 0.633 AC: 6676 AN: 10546

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43705 AN: 67944

Other (OTH) AF: 0.612 AC: 1296 AN: 2116

Alfa AF: 0.601 Hom.: 4819

Bravo AF: 0.601

Asia WGS AF: 0.592 AC: 2057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		0.24
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: rs2044760; hg19: chr2-148989731;