rs747721968
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000528.4(MAN2B1):c.1501T>A(p.Cys501Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,560 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C501C) has been classified as Likely benign.
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.1501T>A | p.Cys501Ser | missense_variant | 12/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.1498T>A | p.Cys500Ser | missense_variant | 12/24 | ||
MAN2B1 | XM_005259913.3 | c.1504T>A | p.Cys502Ser | missense_variant | 12/24 | ||
MAN2B1 | XM_047438841.1 | c.400T>A | p.Cys134Ser | missense_variant | 5/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.1501T>A | p.Cys501Ser | missense_variant | 12/24 | 1 | NM_000528.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250324Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135630
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461350Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727000
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 03, 2021 | - - |
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 07, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2021 | Variant summary: MAN2B1 c.1501T>A (p.Cys501Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250324 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1501T>A has been reported in the literature in an individual affected with Type II - Alpha-Mannosidosis. The individual was compound heterozygous for the variant of interest and another pathogenic variant. However, the variant was also in cis with another variant c.2849G>C p.R950P (Borgwardt_2015). Intra cellular processing, transport and secretion studies in cell culture suggested that single mutations p.C501S and p.R950P were processed and transported to lysosomes but in the combined double variant, no indication of lysosomal localization was noted. The authors further report that whether both mutations were required for the disease development remain unknown (Kuokkanen_2011). 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 uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at