rs370803545
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000528.4(MAN2B1):c.418C>T(p.Arg140*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,607,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
MAN2B1
NM_000528.4 stop_gained
NM_000528.4 stop_gained
Scores
2
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2
Clinical Significance
Conservation
PhyloP100: 2.37
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 19-12665370-G-A is Pathogenic according to our data. Variant chr19-12665370-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 328281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MAN2B1 | NM_000528.4 | c.418C>T | p.Arg140* | stop_gained | 3/24 | ENST00000456935.7 | NP_000519.2 | |
| MAN2B1 | NM_001173498.2 | c.418C>T | p.Arg140* | stop_gained | 3/24 | NP_001166969.1 | ||
| MAN2B1 | XM_005259913.3 | c.418C>T | p.Arg140* | stop_gained | 3/24 | XP_005259970.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000163 AC: 4AN: 245868Hom.: 0 AF XY: 0.0000300 AC XY: 4AN XY: 133234
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GnomAD4 exome AF: 0.00000893 AC: 13AN: 1455722Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 724408
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GnomAD4 genome 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:8
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 19, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The MAN2B1 c.418C>T (p.Arg140Ter) variant is a stop-gained variant and has been reported in at least two studies in which it is found in at least three individuals with alpha-mannosidosis including one in a homozygous state and two in a compound heterozygous state with a missense variant on the second allele (Stensland H et al. 2012; Borgwardt et al. 2015). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Arg140Ter variant is classified as likely pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 23, 2023 | This sequence change creates a premature translational stop signal (p.Arg140*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with mannosidosis (PMID: 22161967, 26048034). ClinVar contains an entry for this variant (Variation ID: 328281). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2018 | Variant summary: MAN2B1 c.418C>T (p.Arg140X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.7e-05 in 240946 control chromosomes (gnomAD). The variant, c.418C>T, has been reported in the literature in individuals affected with Alpha-Mannosidosis, in both compound heterozygotes and one homozygote (Borgwardt_2015, RiseStensland_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -18
Find out detailed SpliceAI scores and Pangolin per-transcript scores at