rs1555706706
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000528.4(MAN2B1):c.2212del(p.Glu738ArgfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 30)
Consequence
MAN2B1
NM_000528.4 frameshift
NM_000528.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0110
Genes affected
MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-12649967-TC-T is Pathogenic according to our data. Variant chr19-12649967-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 520823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.2212del | p.Glu738ArgfsTer28 | frameshift_variant | 18/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.2209del | p.Glu737ArgfsTer28 | frameshift_variant | 18/24 | ||
MAN2B1 | XM_005259913.3 | c.2215del | p.Glu739ArgfsTer28 | frameshift_variant | 18/24 | ||
MAN2B1 | XM_047438841.1 | c.1111del | p.Glu371ArgfsTer28 | frameshift_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2212del | p.Glu738ArgfsTer28 | frameshift_variant | 18/24 | 1 | NM_000528.4 | A1 | |
MAN2B1 | ENST00000221363.8 | c.2209del | p.Glu737ArgfsTer28 | frameshift_variant | 18/24 | 1 | P4 | ||
MAN2B1 | ENST00000466794.5 | n.2802del | non_coding_transcript_exon_variant | 16/22 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2015 | - - |
Deficiency of alpha-mannosidase Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at