rs772108001
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_000528.4(MAN2B1):c.598C>A(p.His200Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,680 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. H200L) 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 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.598C>A | p.His200Asn | missense_variant | 4/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.598C>A | p.His200Asn | missense_variant | 4/24 | ||
MAN2B1 | XM_005259913.3 | c.598C>A | p.His200Asn | missense_variant | 4/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.598C>A | p.His200Asn | missense_variant | 4/24 | 1 | NM_000528.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249180Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134970
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461424Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726988
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:2Uncertain:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 13, 2022 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His200 amino acid residue in MAN2B1. Other variant(s) that disrupt this residue have been observed in individuals with MAN2B1-related conditions (PMID: 22161967, 26048034), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 16919251, 21505070, 22161967). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 208255). This missense change has been observed in individual(s) with alpha mannosidosis (PMID: 16919251, 22161967, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs772108001, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 200 of the MAN2B1 protein (p.His200Asn). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 05, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at