19-12665743-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000528.4(MAN2B1):c.222C>A(p.Asp74Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,026 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.222C>A | p.Asp74Glu | missense_variant | Exon 2 of 24 | ENST00000456935.7 | NP_000519.2 | |
MAN2B1 | NM_001173498.2 | c.222C>A | p.Asp74Glu | missense_variant | Exon 2 of 24 | NP_001166969.1 | ||
MAN2B1 | XM_005259913.3 | c.222C>A | p.Asp74Glu | missense_variant | Exon 2 of 24 | XP_005259970.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.222C>A | p.Asp74Glu | missense_variant | Exon 2 of 24 | 1 | NM_000528.4 | ENSP00000395473.2 | ||
ENSG00000269590 | ENST00000597961.1 | c.213C>A | p.Asp71Glu | missense_variant | Exon 3 of 5 | 4 | ENSP00000472710.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:2Uncertain:1
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Variant summary: MAN2B1 c.222C>A (p.Asp74Glu) results in a conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of 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 2e-05 in 251662 control chromosomes (gnomAD and publication data). c.222C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis or suspected mitochondrial disorders (Riise Stensland_2012, Lieber_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies reported this variant has dramatically reduced alpha-mannosidase activity in transfected cells and was both proteolytically processed and extracellularly secreted, but less efficiently than the wild-type (Kuokkanen_2011, Riise Stensland_2012, Riise Stensland_2015). One ClinVar submitter (evaluation after 2014) cites this variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect (absent alpha-mannosidase activity) (PMID: 22161967); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21505070, Mandl2024[Computational], 31775018, 38107468, 39976451, 22161967) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at