rs373240866

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_000528.4(MAN2B1):c.2249G>A(p.Arg750Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,534 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R750W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.09

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-12649932-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

PP5

Variant 19-12649931-C-T is Pathogenic according to our data. Variant chr19-12649931-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587572.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAN2B1	NM_000528.4 linkuse as main transcript	c.2249G>A	p.Arg750Gln	missense_variant	18/24	ENST00000456935.7
MAN2B1	NM_001173498.2 linkuse as main transcript	c.2246G>A	p.Arg749Gln	missense_variant	18/24
MAN2B1	XM_005259913.3 linkuse as main transcript	c.2252G>A	p.Arg751Gln	missense_variant	18/24
MAN2B1	XM_047438841.1 linkuse as main transcript	c.1148G>A	p.Arg383Gln	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7 linkuse as main transcript	c.2249G>A	p.Arg750Gln	missense_variant	18/24	1	NM_000528.4	A1	O00754-1
MAN2B1	ENST00000221363.8 linkuse as main transcript	c.2246G>A	p.Arg749Gln	missense_variant	18/24	1		P4	O00754-2
MAN2B1	ENST00000466794.5 linkuse as main transcript	n.2839G>A		non_coding_transcript_exon_variant	16/22	2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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:

0.0000119

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

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:

0.000142

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 750 of the MAN2B1 protein (p.Arg750Gln). This variant is present in population databases (rs373240866, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 587572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. This variant disrupts the p.Arg750 amino acid residue in MAN2B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9758606, 9915946, 15035660, 22161967). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.16

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.84

MVP

0.85

MPC

0.93

ClinPred

0.99

GERP RS

2.9

Varity_R

0.82

gMVP

0.82

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over