NM_000528.4:c.2426T>C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000528.4(MAN2B1):c.2426T>C(p.Leu809Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000887 in 1,612,018 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 (★★).
Frequency
Consequence
NM_000528.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MAN2B1 | NM_000528.4 | c.2426T>C | p.Leu809Pro | missense_variant | Exon 20 of 24 | ENST00000456935.7 | NP_000519.2 | |
MAN2B1 | NM_001173498.2 | c.2423T>C | p.Leu808Pro | missense_variant | Exon 20 of 24 | NP_001166969.1 | ||
MAN2B1 | XM_005259913.3 | c.2429T>C | p.Leu810Pro | missense_variant | Exon 20 of 24 | XP_005259970.1 | ||
MAN2B1 | XM_047438841.1 | c.1325T>C | p.Leu442Pro | missense_variant | Exon 13 of 17 | XP_047294797.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2426T>C | p.Leu809Pro | missense_variant | Exon 20 of 24 | 1 | NM_000528.4 | ENSP00000395473.2 | ||
MAN2B1 | ENST00000221363.8 | c.2423T>C | p.Leu808Pro | missense_variant | Exon 20 of 24 | 1 | ENSP00000221363.4 | |||
MAN2B1 | ENST00000466794.5 | n.3016T>C | non_coding_transcript_exon_variant | Exon 18 of 22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152156Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251186Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135786
GnomAD4 exome AF: 0.0000925 AC: 135AN: 1459862Hom.: 0 Cov.: 33 AF XY: 0.0000909 AC XY: 66AN XY: 726240
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152156Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74322
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:11Uncertain:1Other:1
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PM3_Strong, PS3, PP3, PM2 -
Variant summary: MAN2B1 c.2426T>C (p.Leu809Pro) results in a non-conservative amino acid change located in the glycosyl hydrolase family-38 C-terminal domain (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 6.9e-05 in 277176 control chromosomes (gnomAD and publication controls). This frequency is not higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (6.9e-05 vs 0.0016), allowing no conclusion about variant significance. The variant, c.2426T>C, has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Berg 1999, Borgwardt 2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <10% of normal activity (Berg 1999, Hansen 2004). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 809 of the MAN2B1 protein (p.Leu809Pro). This variant is present in population databases (rs80338681, gnomAD 0.01%). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 9915946, 22161967, 23613340, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21210). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 9915946, 15035660). For these reasons, this variant has been classified as Pathogenic. -
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This sequence variant is a single nucleotide substitution (T>C) at position 2426 of the coding sequence of the MAN2B1 gene that results in a leucine to proline amino acid change at residue 809 of the mannosidase alpha class 2B member 1 protein. This is a previously reported variant (ClinVar 21210) that has been observed in homozygous and compound heterozygous individuals affected by alpha-mannosidosis (PMID: 22161967, 9915946, 15035660, 26048034). This variant is present in 25 of 403342 alleles (0.0062%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this Leu to Pro amino acid change would be damaging, and the Leu809 residue at this position is highly conserved across the vertebrate species examined. The activity of the variant protein is significantly reduced when expressed in cultured fibroblasts and COS cells (PMID: 9915946, 15035660). This is likely due to the misfolding of the protein resulting its retention in the endoplasmic reticulum (PMID: 15035660, 26048034). Given this information, we consider this a likely pathogenic variant. ACMG Criteria: PM3, PP3, PS3 -
MAN2B1-related disorder Pathogenic:1
The MAN2B1 c.2426T>C variant is predicted to result in the amino acid substitution p.Leu809Pro. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with alpha-mannosidosis (see for example Berg. et al. 1999. PubMed ID: 9915946; Borgwardt. et al. 2015. PubMed ID: 26048034). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is interpreted as pathogenic in ClinVar by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/21210/). This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at