19-12650129-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000528.4(MAN2B1):c.2140T>C(p.Trp714Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,646 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 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 8.35

Publications

4 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)

MAN2B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 19-12650129-A-G is Pathogenic according to our data. Variant chr19-12650129-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.2140T>C	p.Trp714Arg	missense_variant	Exon 17 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.2143T>C	p.Trp715Arg	missense_variant	Exon 17 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.2137T>C	p.Trp713Arg	missense_variant	Exon 17 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_047438841.1 link	c.1039T>C	p.Trp347Arg	missense_variant	Exon 10 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAN2B1	ENST00000456935.7 link	c.2140T>C	p.Trp714Arg	missense_variant	Exon 17 of 24	1	NM_000528.4	ENSP00000395473.2	O00754-1
MAN2B1	ENST00000221363.9 link	c.2137T>C	p.Trp713Arg	missense_variant	Exon 17 of 24	1		ENSP00000221363.4	O00754-2
MAN2B1	ENST00000466794.5 link	n.2730T>C		non_coding_transcript_exon_variant	Exon 15 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151808

Hom.:

Cov.:

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151808

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41294

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Pathogenic:5Uncertain:1

Apr 04, 2024

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.2140T>C (p.Trp714Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 38, C-terminal (IPR011682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251456 control chromosomes. c.2140T>C has been reported in the literature in individuals affected with Alpha-Mannosidosis (Berg_1999, Riise_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating defective protein transport and activity (Hansen_2004). ClinVar contains an entry for this variant (Variation ID: 208284). 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

- -

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 714 of the MAN2B1 protein (p.Trp714Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 9915946, 22161967). ClinVar contains an entry for this variant (Variation ID: 208284). 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. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 15035660). 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. -

Nov 10, 2021

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant classified as likely pathogenic in the context of alpha-mannosidosis. W714R has been observed in cases with relevant disease (PMID: 9915946, 22161967). Functional assessments of this variant are available in the literature (PMID: 15035660). Internal structural analysis of the variant is supportive of pathogenicity. W714R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jun 23, 2017

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.7

H;.

PhyloP100

8.4

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-12

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.92

Gain of disorder (P = 0.0037);.;

MVP

0.96

MPC

1.2

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.86

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over