2-148512905-AC-ACC
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_001378120.1(MBD5):c.5154dup(p.Lys1719GlnfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000248 in 1,613,516 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MBD5
NM_001378120.1 frameshift
NM_001378120.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.71
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
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Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2278 codons.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MBD5 | NM_001378120.1 | c.5154dup | p.Lys1719GlnfsTer22 | frameshift_variant | 14/14 | ENST00000642680.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MBD5 | ENST00000642680.2 | c.5154dup | p.Lys1719GlnfsTer22 | frameshift_variant | 14/14 | NM_001378120.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151804Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251276Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135816
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461712Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727158
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 2415055). This variant has not been reported in the literature in individuals affected with MBD5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change results in a frameshift in the MBD5 gene (p.Lys1486Glnfs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the MBD5 protein and extend the protein by 12 additional amino acid residues. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at