rs1406466561
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000528.4(MAN2B1):āc.2669C>Gā(p.Ser890Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S890S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000528.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.2669C>G | p.Ser890Ter | stop_gained | 22/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.2666C>G | p.Ser889Ter | stop_gained | 22/24 | ||
MAN2B1 | XM_005259913.3 | c.2672C>G | p.Ser891Ter | stop_gained | 22/24 | ||
MAN2B1 | XM_047438841.1 | c.1568C>G | p.Ser523Ter | stop_gained | 15/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2669C>G | p.Ser890Ter | stop_gained | 22/24 | 1 | NM_000528.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460368Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726404
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 02, 2019 | Variant summary: MAN2B1 c.2669C>G (p.Ser890X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245278 control chromosomes (gnomAD). c.2669C>G has been reported in the literature in compound heterozygote individuals affected with Alpha-Mannosidosis (Rise Stensland_2012). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 27, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552770). This premature translational stop signal has been observed in individuals with mannosidosis (PMID: 22161967). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser890*) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at