NM_000528.4:c.2921_2922delCA
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_000528.4(MAN2B1):c.2921_2922delCA(p.Thr974ArgfsTer74) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MAN2B1
NM_000528.4 frameshift, splice_region
NM_000528.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0660
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]
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)
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-12647233-CTG-C is Pathogenic according to our data. Variant chr19-12647233-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551633.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MAN2B1 | NM_000528.4 | c.2921_2922delCA | p.Thr974ArgfsTer74 | frameshift_variant, splice_region_variant | Exon 23 of 24 | ENST00000456935.7 | NP_000519.2 | |
| MAN2B1 | NM_001440570.1 | c.2924_2925delCA | p.Thr975ArgfsTer74 | frameshift_variant, splice_region_variant | Exon 23 of 24 | NP_001427499.1 | ||
| MAN2B1 | NM_001173498.2 | c.2918_2919delCA | p.Thr973ArgfsTer74 | frameshift_variant, splice_region_variant | Exon 23 of 24 | NP_001166969.1 | ||
| MAN2B1 | XM_047438841.1 | c.1820_1821delCA | p.Thr607ArgfsTer74 | frameshift_variant, splice_region_variant | Exon 16 of 17 | XP_047294797.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MAN2B1 | ENST00000456935.7 | c.2921_2922delCA | p.Thr974ArgfsTer74 | frameshift_variant, splice_region_variant | Exon 23 of 24 | 1 | NM_000528.4 | ENSP00000395473.2 | ||
| ENSG00000269242 | ENST00000597692.1 | n.479_480delCA | splice_region_variant, non_coding_transcript_exon_variant | Exon 3 of 5 | 2 | ENSP00000470240.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461080Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726890 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461080
Hom.:
AF XY:
AC XY:
1
AN XY:
726890
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33456
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111276
Other (OTH)
AF:
AC:
0
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
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Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:1
Apr 20, 2017
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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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