rs778399351
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000528.4(MAN2B1):c.422del(p.Asp141AlafsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Consequence
MAN2B1
NM_000528.4 frameshift
NM_000528.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.840
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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;
PP5
?
Variant 19-12665365-GT-G is Pathogenic according to our data. Variant chr19-12665365-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.422del | p.Asp141AlafsTer16 | frameshift_variant | 3/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.422del | p.Asp141AlafsTer16 | frameshift_variant | 3/24 | ||
MAN2B1 | XM_005259913.3 | c.422del | p.Asp141AlafsTer16 | frameshift_variant | 3/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.422del | p.Asp141AlafsTer16 | frameshift_variant | 3/24 | 1 | NM_000528.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1
AN:
152184
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000408 AC: 1AN: 245084Hom.: 0 AF XY: 0.00000753 AC XY: 1AN XY: 132876
GnomAD3 exomes
AF:
AC:
1
AN:
245084
Hom.:
AF XY:
AC XY:
1
AN XY:
132876
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348
GnomAD4 genome
?
AF:
AC:
1
AN:
152184
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74348
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 16, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 21, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371425). This premature translational stop signal has been observed in individual(s) with mannosidosis (PMID: 22161967). This variant is present in population databases (rs778399351, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asp141Alafs*16) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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