rs141212446
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000528.4(MAN2B1):c.2260G>A(p.Glu754Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,084 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000528.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.2260G>A | p.Glu754Lys | missense_variant | 18/24 | ENST00000456935.7 | |
MAN2B1 | NM_001173498.2 | c.2257G>A | p.Glu753Lys | missense_variant | 18/24 | ||
MAN2B1 | XM_005259913.3 | c.2263G>A | p.Glu755Lys | missense_variant | 18/24 | ||
MAN2B1 | XM_047438841.1 | c.1159G>A | p.Glu387Lys | missense_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2260G>A | p.Glu754Lys | missense_variant | 18/24 | 1 | NM_000528.4 | A1 | |
MAN2B1 | ENST00000221363.8 | c.2257G>A | p.Glu753Lys | missense_variant | 18/24 | 1 | P4 | ||
MAN2B1 | ENST00000466794.5 | n.2850G>A | non_coding_transcript_exon_variant | 16/22 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00129 AC: 196AN: 151856Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00123 AC: 309AN: 251484Hom.: 2 AF XY: 0.00115 AC XY: 156AN XY: 135914
GnomAD4 exome AF: 0.00177 AC: 2592AN: 1461112Hom.: 7 Cov.: 34 AF XY: 0.00175 AC XY: 1274AN XY: 726876
GnomAD4 genome ? AF: 0.00129 AC: 196AN: 151972Hom.: 0 Cov.: 30 AF XY: 0.00123 AC XY: 91AN XY: 74272
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 16, 2023 | BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | MAN2B1: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 27, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: MAN2B1 c.2260G>A (p.Glu754Lys) results in a conservative amino acid change located in the Glycosyl hydrolase family 38, C-terminal (IPR011682) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251484 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2260G>A in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
MAN2B1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 11, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at