2-148178801-G-GT

Variant names:

• chr2-148178801-G-GT
• rs796052705
• NM_001378120.1:c.-831+9dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001378120.1(MBD5):​c.-831+9dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 398,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.617
• 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 -9 ACMG points.

• BP6: Variant 2-148178801-G-GT is Benign according to our data. Variant chr2-148178801-G-GT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206049.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000565 (86/152138) while in subpopulation NFE AF = 0.0011 (75/68022). AF 95% confidence interval is 0.000902. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-831+9dupT		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.-831+8_-831+9insT		intron_variant	Intron 2 of 13		NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000736 AC: 181 AN: 246044 Hom.: 0 Cov.: 0 AF XY: 0.000762 AC XY: 95 AN XY: 124750

African (AFR) AF: 0.000140 AC: 1 AN: 7156

American (AMR) AF: 0.000135 AC: 1 AN: 7426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9206

East Asian (EAS) AF: 0.00 AC: 0 AN: 22714

South Asian (SAS) AF: 0.00 AC: 0 AN: 3014

European-Finnish (FIN) AF: 0.000471 AC: 10 AN: 21214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1286

European-Non Finnish (NFE) AF: 0.00103 AC: 162 AN: 157690

Other (OTH) AF: 0.000428 AC: 7 AN: 16338

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.000444 AC XY: 33 AN XY: 74326

African (AFR) AF: 0.0000966 AC: 4 AN: 41422

American (AMR) AF: 0.000328 AC: 5 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.000423

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual Disability, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 24, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in INFANT-EPI,EPILEPSY panel(s). -

not provided Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBD5: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62

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: rs796052705; hg19: chr2-148936370;