rs1290585382
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000456935.7(MAN2B1):c.1_2delAT(p.Met1GlyfsTer72) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,396,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Consequence
MAN2B1
ENST00000456935.7 frameshift, start_lost
ENST00000456935.7 frameshift, start_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.12
Publications
0 publications found
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]
WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 271 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000456935.7. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MAN2B1 | NM_000528.4 | MANE Select | c.1_2delAT | p.Met1GlyfsTer72 | frameshift start_lost | Exon 1 of 24 | NP_000519.2 | ||
| MAN2B1 | NM_001440570.1 | c.1_2delAT | p.Met1GlyfsTer72 | frameshift start_lost | Exon 1 of 24 | NP_001427499.1 | |||
| MAN2B1 | NM_001173498.2 | c.1_2delAT | p.Met1GlyfsTer72 | frameshift start_lost | Exon 1 of 24 | NP_001166969.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MAN2B1 | ENST00000456935.7 | TSL:1 MANE Select | c.1_2delAT | p.Met1GlyfsTer72 | frameshift start_lost | Exon 1 of 24 | ENSP00000395473.2 | ||
| MAN2B1 | ENST00000221363.9 | TSL:1 | c.1_2delAT | p.Met1GlyfsTer72 | frameshift start_lost | Exon 1 of 24 | ENSP00000221363.4 | ||
| ENSG00000269590 | ENST00000597961.1 | TSL:4 | c.151-896_151-895delAT | intron | N/A | ENSP00000472710.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.00000685 AC: 1AN: 146048 AF XY: 0.0000127 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
146048
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000286 AC: 4AN: 1396474Hom.: 0 AF XY: 0.00000145 AC XY: 1AN XY: 688776 show subpopulations
GnomAD4 exome
AF:
AC:
4
AN:
1396474
Hom.:
AF XY:
AC XY:
1
AN XY:
688776
show subpopulations
African (AFR)
AF:
AC:
0
AN:
31574
American (AMR)
AF:
AC:
0
AN:
35702
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25136
East Asian (EAS)
AF:
AC:
4
AN:
35788
South Asian (SAS)
AF:
AC:
0
AN:
79234
European-Finnish (FIN)
AF:
AC:
0
AN:
47878
Middle Eastern (MID)
AF:
AC:
0
AN:
4706
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1078632
Other (OTH)
AF:
AC:
0
AN:
57824
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.538
Heterozygous variant carriers
0
0
1
1
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2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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<30
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Uncertain significance
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
-
1
-
Deficiency of alpha-mannosidase (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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