rs772853856
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000528.4(MAN2B1):c.1259G>T(p.Gly420Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,386 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. G420D) 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 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.1259G>T | p.Gly420Val | missense_variant | 10/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.1256G>T | p.Gly419Val | missense_variant | 10/24 | ||
MAN2B1 | XM_005259913.3 | c.1262G>T | p.Gly421Val | missense_variant | 10/24 | ||
MAN2B1 | XM_047438841.1 | c.158G>T | p.Gly53Val | missense_variant | 3/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.1259G>T | p.Gly420Val | missense_variant | 10/24 | 1 | NM_000528.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249208Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135392
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461216Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726916
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:1Uncertain:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 26, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 420 of the MAN2B1 protein (p.Gly420Val). This variant is present in population databases (rs772853856, gnomAD 0.01%). This missense change has been observed in individual(s) with leukodystrophy (PMID: 17404523). ClinVar contains an entry for this variant (Variation ID: 208264). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 21505070, 22161967). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 07, 2022 | - - |
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 07, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at