rs61737536
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000528.4(MAN2B1):c.747C>T(p.Thr249=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,612,522 control chromosomes in the GnomAD database, including 1,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.050 ( 634 hom., cov: 32)
Exomes 𝑓: 0.0052 ( 612 hom. )
Consequence
MAN2B1
NM_000528.4 synonymous
NM_000528.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.20
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
?
Variant 19-12663719-G-A is Benign according to our data. Variant chr19-12663719-G-A is described in ClinVar as [Benign]. Clinvar id is 197683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12663719-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-3.2 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.747C>T | p.Thr249= | synonymous_variant | 5/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.747C>T | p.Thr249= | synonymous_variant | 5/24 | ||
MAN2B1 | XM_005259913.3 | c.747C>T | p.Thr249= | synonymous_variant | 5/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.747C>T | p.Thr249= | synonymous_variant | 5/24 | 1 | NM_000528.4 | A1 | |
MAN2B1 | ENST00000221363.8 | c.747C>T | p.Thr249= | synonymous_variant | 5/24 | 1 | P4 | ||
MAN2B1 | ENST00000486847.2 | c.450C>T | p.Thr150= | synonymous_variant | 3/4 | 4 | |||
MAN2B1 | ENST00000466794.5 | n.729C>T | non_coding_transcript_exon_variant | 5/22 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0502 AC: 7637AN: 152142Hom.: 635 Cov.: 32
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GnomAD3 exomes AF: 0.0133 AC: 3267AN: 246476Hom.: 274 AF XY: 0.00949 AC XY: 1270AN XY: 133808
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GnomAD4 exome AF: 0.00517 AC: 7554AN: 1460262Hom.: 612 Cov.: 32 AF XY: 0.00451 AC XY: 3274AN XY: 726444
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of alpha-mannosidase Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 21, 2017 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 09, 2015 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at