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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

11
5
3

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: -0.150
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.904
PP5
Variant 19-12665743-G-T is Pathogenic according to our data. Variant chr19-12665743-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12665743-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAN2B1NM_000528.4 linkc.222C>A p.Asp74Glu missense_variant Exon 2 of 24 ENST00000456935.7 NP_000519.2 O00754-1
MAN2B1NM_001173498.2 linkc.222C>A p.Asp74Glu missense_variant Exon 2 of 24 NP_001166969.1 O00754-2A8K6A7
MAN2B1XM_005259913.3 linkc.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
MAN2B1ENST00000456935.7 linkc.222C>A p.Asp74Glu missense_variant Exon 2 of 24 1 NM_000528.4 ENSP00000395473.2 O00754-1
ENSG00000269590ENST00000597961.1 linkc.213C>A p.Asp71Glu missense_variant Exon 3 of 5 4 ENSP00000472710.1 M0R2P5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251462
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135912
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000439
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461854
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000648
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:2Uncertain:1
Jan 06, 2024
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 16, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 07, 2012
ClinVar Staff, National Center for Biotechnology Information (NCBI)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
Mar 11, 2025
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.47
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D;.;.;.
Eigen
Uncertain
0.34
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.8
H;H;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.5
D;D;.;.
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.96
MutPred
0.93
Gain of ubiquitination at K79 (P = 0.2122);Gain of ubiquitination at K79 (P = 0.2122);.;.;
MVP
0.93
MPC
1.5
ClinPred
1.0
D
GERP RS
-3.8
Varity_R
0.91
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746702002; hg19: chr19-12776557; API