rs864621994
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000528.4(MAN2B1):c.2402G>A(p.Gly801Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,556 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G801C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000528.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.2402G>A | p.Gly801Asp | missense_variant | 20/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.2399G>A | p.Gly800Asp | missense_variant | 20/24 | ||
MAN2B1 | XM_005259913.3 | c.2405G>A | p.Gly802Asp | missense_variant | 20/24 | ||
MAN2B1 | XM_047438841.1 | c.1301G>A | p.Gly434Asp | missense_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2402G>A | p.Gly801Asp | missense_variant | 20/24 | 1 | NM_000528.4 | A1 | |
MAN2B1 | ENST00000221363.8 | c.2399G>A | p.Gly800Asp | missense_variant | 20/24 | 1 | P4 | ||
MAN2B1 | ENST00000466794.5 | n.2992G>A | non_coding_transcript_exon_variant | 18/22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460308Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726464
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74426
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 07, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 15712269). Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 208285). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 15712269). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 801 of the MAN2B1 protein (p.Gly801Asp). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 22, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19958498, 15712269) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at