chr19-12655693-C-G
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000528.4(MAN2B1):c.1830+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000167 in 1,608,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
MAN2B1
NM_000528.4 splice_donor, intron
NM_000528.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.67
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06126482 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-12655693-C-G is Pathogenic according to our data. Variant chr19-12655693-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 21207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12655693-C-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MAN2B1 | NM_000528.4 | c.1830+1G>C | splice_donor_variant, intron_variant | Intron 14 of 23 | ENST00000456935.7 | NP_000519.2 | ||
| MAN2B1 | NM_001173498.2 | c.1827+1G>C | splice_donor_variant, intron_variant | Intron 14 of 23 | NP_001166969.1 | |||
| MAN2B1 | XM_005259913.3 | c.1833+1G>C | splice_donor_variant, intron_variant | Intron 14 of 23 | XP_005259970.1 | |||
| MAN2B1 | XM_047438841.1 | c.729+1G>C | splice_donor_variant, intron_variant | Intron 7 of 16 | XP_047294797.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000789 AC: 12AN: 152118Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000925 AC: 23AN: 248630Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134398
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GnomAD4 exome AF: 0.000176 AC: 257AN: 1456706Hom.: 0 Cov.: 31 AF XY: 0.000152 AC XY: 110AN XY: 723972
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:12Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 26, 2024 | This sequence change affects a donor splice site in intron 14 of the MAN2B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is present in population databases (rs80338677, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with mannosidosis (PMID: 9915946, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS14+1G>C. ClinVar contains an entry for this variant (Variation ID: 21207). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 02, 2022 | PVS1, PM2, PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 01, 2021 | NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant classified as pathogenic in the context of alpha-mannosidosis. c.1830+1G>C has been observed in cases with relevant disease (PMID: 9915946, 22161967). Functional assessments of this variant are not available in the literature. c.1830+1G>C has been observed in population frequency databases (gnomAD: FIN 0.03%). In summary, NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 22, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 25, 2019 | Variant summary: MAN2B1 c.1830+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 248630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (9.3e-05 vs 0.0016). c.1830+1G>C has been reported in the literature as one of the most common disease causing variants in multiple individuals affected with Alpha-Mannosidosis (example, Riise Stensland_2012, Berg_1999). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained within the context of this evaluation. One clinical diagnostic laboratory has 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 09, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 26, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available, intron 14). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (24 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0704 - Comparable variant has low previous evidence for pathogenicity (Borgwardt, L. et al. (2015); Riise Stensland, H. et al. (2012)). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; Matlach, J. et al (2018)). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2012 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2024 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2017 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2024 | Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9915946, 22161967, 31980526, 34429528, 38382588, 38107468) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at