GeneBe

NM_000528.4:c.935C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000528.4(MAN2B1):​c.935C>G​(p.Thr312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T312N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

1
5
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.96

Publications

49 publications found
Variant links:
Genes affected
MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]
MAN2B1 Gene-Disease associations (from GenCC):
  • alpha-mannosidosis
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32278445).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAN2B1NM_000528.4 linkc.935C>G p.Thr312Ser missense_variant Exon 7 of 24 ENST00000456935.7 NP_000519.2 O00754-1
MAN2B1NM_001440570.1 linkc.935C>G p.Thr312Ser missense_variant Exon 7 of 24 NP_001427499.1
MAN2B1NM_001173498.2 linkc.935C>G p.Thr312Ser missense_variant Exon 7 of 24 NP_001166969.1 O00754-2A8K6A7
MAN2B1XM_047438841.1 linkc.-84C>G 5_prime_UTR_variant Exon 1 of 17 XP_047294797.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAN2B1ENST00000456935.7 linkc.935C>G p.Thr312Ser missense_variant Exon 7 of 24 1 NM_000528.4 ENSP00000395473.2 O00754-1
MAN2B1ENST00000221363.9 linkc.935C>G p.Thr312Ser missense_variant Exon 7 of 24 1 ENSP00000221363.4 O00754-2
MAN2B1ENST00000462144.1 linkn.128C>G non_coding_transcript_exon_variant Exon 2 of 2 3
MAN2B1ENST00000466794.5 linkn.917C>G non_coding_transcript_exon_variant Exon 7 of 22 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251472
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461158
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726938
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33464
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53398
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111388
Other (OTH)
AF:
0.00
AC:
0
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.048
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
15
DANN
Benign
0.83
DEOGEN2
Benign
0.30
T;.
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.94
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.32
T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
0.69
N;N
PhyloP100
2.0
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.6
N;N
REVEL
Uncertain
0.32
Sift
Uncertain
0.0020
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.27
B;.
Vest4
0.29
MutPred
0.63
Gain of disorder (P = 0.0889);Gain of disorder (P = 0.0889);
MVP
0.59
MPC
0.65
ClinPred
0.14
T
GERP RS
-2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.69
Mutation Taster
=96/4
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1054487; hg19: chr19-12772165; API