2-148342583-T-C

Variant names:

• chr2-148342583-T-C
• rs2602352
• NM_001378120.1:c.-557+247T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378120.1(MBD5):​c.-557+247T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 151,708 control chromosomes in the GnomAD database, including 6,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (6539 hom., cov: 31)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.45
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-148342583-T-C is Benign according to our data. Variant chr2-148342583-T-C is described in ClinVar as [Benign]. Clinvar id is 1295206.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-557+247T>C		intron_variant	Intron 4 of 13	ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-557+247T>C		intron_variant	Intron 4 of 13		NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41671 AN: 151590 Hom.: 6528 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.275 AC: 41701 AN: 151708 Hom.: 6539 Cov.: 31 AF XY: 0.276 AC XY: 20429 AN XY: 74120

African (AFR) AF: 0.114 AC: 4717 AN: 41468

American (AMR) AF: 0.367 AC: 5566 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3462

East Asian (EAS) AF: 0.253 AC: 1303 AN: 5150

South Asian (SAS) AF: 0.351 AC: 1687 AN: 4808

European-Finnish (FIN) AF: 0.311 AC: 3264 AN: 10506

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23111 AN: 67838

Other (OTH) AF: 0.280 AC: 589 AN: 2106

Alfa AF: 0.313 Hom.: 1081

Bravo AF: 0.270

Asia WGS AF: 0.335 AC: 1161 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		1.4
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: rs2602352; hg19: chr2-149100152;