rs121434331
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000528.4(MAN2B1):c.2278C>T(p.Arg760*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000621 in 1,610,244 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 Likely pathogenic (★★). 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.2278C>T | p.Arg760* | stop_gained | Exon 19 of 24 | ENST00000456935.7 | NP_000519.2 | |
MAN2B1 | NM_001173498.2 | c.2275C>T | p.Arg759* | stop_gained | Exon 19 of 24 | NP_001166969.1 | ||
MAN2B1 | XM_005259913.3 | c.2281C>T | p.Arg761* | stop_gained | Exon 19 of 24 | XP_005259970.1 | ||
MAN2B1 | XM_047438841.1 | c.1177C>T | p.Arg393* | stop_gained | Exon 12 of 17 | XP_047294797.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2278C>T | p.Arg760* | stop_gained | Exon 19 of 24 | 1 | NM_000528.4 | ENSP00000395473.2 | ||
MAN2B1 | ENST00000221363.8 | c.2275C>T | p.Arg759* | stop_gained | Exon 19 of 24 | 1 | ENSP00000221363.4 | |||
MAN2B1 | ENST00000466794.5 | n.2868C>T | non_coding_transcript_exon_variant | Exon 17 of 22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151274Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248886Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134638
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1458970Hom.: 0 Cov.: 32 AF XY: 0.00000827 AC XY: 6AN XY: 725800
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151274Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2AN XY: 73842
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:7
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This sequence change creates a premature translational stop signal (p.Arg760*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of mannosidosis (PMID: 9758606). ClinVar contains an entry for this variant (Variation ID: 1685). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: The MAN2B1 c.2278C>T (p.Arg760X) variant results in a premature termination codon, predicted to cause a truncated or absent MAN2B1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/108116 (1/54058), which does not exceed the estimated maximal expected allele frequency for a pathogenic MAN2B1 variant of 1/632. A publication, Godota_1998, cites the variant in a sibling pair, where both sisters were homozygous for the variant. Authors indicate that the variant causes a Lysosomal alpha-mannosidosis type 2, with a milder phenotype, hypothesized by "The nonsense mutation in the alpha-mannosidase gene is located in exon 19, at a point ~75% along the length of the protein. This nonsense mutation likely encodes an unstable mRNA, such that a relatively stable but defective protein is produced that can show partial activity toward alpha-mannose residues in vivo." In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at