chr19-12649169-GC-G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000528.4(MAN2B1):c.2402delG(p.Gly801AlafsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,612,486 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MAN2B1
NM_000528.4 frameshift
NM_000528.4 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 4.59
Publications
4 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]
MAN2B1 Gene-Disease associations (from GenCC):
- alpha-mannosidosisInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 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;
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000528.4. 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.2402delG | p.Gly801AlafsTer4 | frameshift | Exon 20 of 24 | NP_000519.2 | ||
| MAN2B1 | NM_001440570.1 | c.2405delG | p.Gly802AlafsTer4 | frameshift | Exon 20 of 24 | NP_001427499.1 | |||
| MAN2B1 | NM_001173498.2 | c.2399delG | p.Gly800AlafsTer4 | frameshift | Exon 20 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.2402delG | p.Gly801AlafsTer4 | frameshift | Exon 20 of 24 | ENSP00000395473.2 | ||
| MAN2B1 | ENST00000221363.9 | TSL:1 | c.2399delG | p.Gly800AlafsTer4 | frameshift | Exon 20 of 24 | ENSP00000221363.4 | ||
| MAN2B1 | ENST00000466794.5 | TSL:2 | n.2992delG | non_coding_transcript_exon | Exon 18 of 22 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152120
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad ASJ
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251348 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
251348
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460366Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726486 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460366
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
726486
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33430
American (AMR)
AF:
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86180
European-Finnish (FIN)
AF:
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
AC:
0
AN:
4552
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111982
Other (OTH)
AF:
AC:
0
AN:
60252
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74314 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152120
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74314
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41428
American (AMR)
AF:
AC:
0
AN:
15258
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5188
South Asian (SAS)
AF:
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68012
Other (OTH)
AF:
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
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Calibrated prediction
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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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