2-148458195-T-C

Variant names:

• chr2-148458195-T-C
• rs140968376
• NM_001378120.1:c.-556-8T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001378120.1(MBD5):​c.-556-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 400,324 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (1 hom.)
• Consequence: MBD5 NM_001378120.1 splice_region, intron
• Scores: Splicing: ADA: 0.006506
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.87
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-148458195-T-C is Benign according to our data. Variant chr2-148458195-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 138171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00343 (522/152330) while in subpopulation AMR AF = 0.00543 (83/15282). AF 95% confidence interval is 0.00487. There are 3 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-556-8T>C		splice_region_variant, 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.-556-8T>C		splice_region_variant, intron_variant	Intron 4 of 13		NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152212 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00371 AC: 921 AN: 247994 Hom.: 1 Cov.: 0 AF XY: 0.00360 AC XY: 453 AN XY: 125678

African (AFR) AF: 0.000841 AC: 6 AN: 7134

American (AMR) AF: 0.00415 AC: 33 AN: 7954

Ashkenazi Jewish (ASJ) AF: 0.000543 AC: 5 AN: 9212

East Asian (EAS) AF: 0.00 AC: 0 AN: 22916

South Asian (SAS) AF: 0.000311 AC: 1 AN: 3214

European-Finnish (FIN) AF: 0.00254 AC: 53 AN: 20826

Middle Eastern (MID) AF: 0.00388 AC: 5 AN: 1288

European-Non Finnish (NFE) AF: 0.00471 AC: 749 AN: 159038

Other (OTH) AF: 0.00420 AC: 69 AN: 16412

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152330 Hom.: 3 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74484

African (AFR) AF: 0.000914 AC: 38 AN: 41586

American (AMR) AF: 0.00543 AC: 83 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00409 Hom.: 0

Bravo AF: 0.00351

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 05, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBD5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		2.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0065
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.16		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: rs140968376; hg19: chr2-149215764;