rs763257568

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000528.4(MAN2B1):c.685C>T(p.Arg229Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,052 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 3.40

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 19-12663781-G-A is Pathogenic according to our data. Variant chr19-12663781-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12663781-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001173498.2 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_005259913.3 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAN2B1	ENST00000456935.7 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 24	1	NM_000528.4	ENSP00000395473.2	O00754-1
MAN2B1	ENST00000221363.8 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 5 of 24	1		ENSP00000221363.4	O00754-2
MAN2B1	ENST00000486847.2 link	c.388C>T	p.Arg130Trp	missense_variant	Exon 3 of 4	4		ENSP00000470174.1	M0QYZ1
MAN2B1	ENST00000466794.5 link	n.667C>T		non_coding_transcript_exon_variant	Exon 5 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000159

AC:

AN:

251450

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000187

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000688

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Pathogenic:7Uncertain:1

Apr 14, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAN2B1 c.685C>T (p.Arg229Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251450 control chromosomes (gnomAD). c.685C>T has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Rise Stensland_2012, Mkaouar_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Berg_2002, Rise Stensland_2012, Mkaouar_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 10, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2012

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685C>T;p.(Arg229Trp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208258; PMID: 26048034; 22161967; 11959458; 21505070) - PS4_moderate.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11959458) - PS3_moderate. The variant is present at low allele frequencies population databases (rs763257568– gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg229Trp) was detected in trans with a Pathogenic variant (PMID: 26048034) - PM3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the MAN2B1 protein (p.Arg229Trp). This variant is present in population databases (rs763257568, gnomAD 0.007%). This missense change has been observed in individual(s) with mannosidosis (PMID: 22161967, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208258). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 11959458, 22161967). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Dec 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with the presence of the variant resulting in a significant reduction in enzyme activity (Riise Stensland et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11959458, 35871018, 22161967, 21505070, 34614013, 26048034) -

MAN2B1-related disorder

Pathogenic:1

Jun 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MAN2B1 c.685C>T variant is predicted to result in the amino acid substitution p.Arg229Trp. This variant has been reported in the homozygous state or heterozygous state with a second MAN2B1 variant in individuals with alpha-mannosidosis (Riise Stensland et al. 2012. PubMed ID: 22161967; Mkaouar et al. 2021. PubMed ID: 34614013). Functional studies have shown this variant does not impact MANB1 maturation and transportation; however, it was reported to reduce the enzymatic activity to 20-30% of the wildtype enzyme which may correlate with a moderate clinical subtype of the disease (Riise Stensland et al. 2012. PubMed ID: 22161967; Kuokkanen et al. 2011. PubMed ID: 21505070). The intra-familial variability of cognitive impairment has been suggested to be associated with pathogenic variants in other genes (Mkaouar et al. 2021. PubMed ID: 34614013). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.7

H;H;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.0

D;D;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.010

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.94

MutPred

0.70

Loss of MoRF binding (P = 0.0387);Loss of MoRF binding (P = 0.0387);.;

MVP

0.94

MPC

1.5

ClinPred

0.94

GERP RS

4.9

Varity_R

0.83

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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