NM_000528.4:c.832C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000528.4(MAN2B1):c.832C>G(p.Leu278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,613,786 control chromosomes in the GnomAD database, including 65,081 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L278M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 7350 hom., cov: 31)

Exomes 𝑓: 0.27 ( 57731 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.440

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.7047944E-4).

BP6

Variant 19-12663394-G-C is Benign according to our data. Variant chr19-12663394-G-C is described in ClinVar as [Benign]. Clinvar id is 93217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12663394-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.832C>G	p.Leu278Val	missense_variant	Exon 6 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001173498.2 link	c.832C>G	p.Leu278Val	missense_variant	Exon 6 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_005259913.3 link	c.832C>G	p.Leu278Val	missense_variant	Exon 6 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.832C>G	p.Leu278Val	missense_variant	Exon 6 of 24	1	NM_000528.4	ENSP00000395473.2		O00754-1

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45332

AN:

151826

Hom.:

7348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.383

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.286

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.266

GnomAD3 exomes

AF:

0.251

AC:

62983

AN:

251424

Hom.:

9032

AF XY:

0.252

AC XY:

34233

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.385

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.295

Gnomad EAS exome

AF:

0.0307

Gnomad SAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.350

Gnomad NFE exome

AF:

0.293

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.274

AC:

400759

AN:

1461842

Hom.:

57731

Cov.:

AF XY:

0.272

AC XY:

198100

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.388

Gnomad4 AMR exome

AF:

0.157

Gnomad4 ASJ exome

AF:

0.298

Gnomad4 EAS exome

AF:

0.0301

Gnomad4 SAS exome

AF:

0.180

Gnomad4 FIN exome

AF:

0.344

Gnomad4 NFE exome

AF:

0.287

Gnomad4 OTH exome

AF:

0.270

GnomAD4 genome

AF:

0.299

AC:

45360

AN:

151944

Hom.:

7350

Cov.:

AF XY:

0.295

AC XY:

21932

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.383

Gnomad4 AMR

AF:

0.192

Gnomad4 ASJ

AF:

0.286

Gnomad4 EAS

AF:

0.0305

Gnomad4 SAS

AF:

0.172

Gnomad4 FIN

AF:

0.353

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.264

Alfa

AF:

0.284

Hom.:

4846

Bravo

AF:

0.291

TwinsUK

AF:

0.287

AC:

1063

ALSPAC

AF:

0.289

AC:

1114

ESP6500AA

AF:

0.376

AC:

1655

ESP6500EA

AF:

0.289

AC:

2488

ExAC

AF:

0.257

AC:

31144

Asia WGS

AF:

0.120

AC:

417

AN:

3478

EpiCase

AF:

0.291

EpiControl

AF:

0.293

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, ClinVar assertions are B/LB -

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Deficiency of alpha-mannosidase

Benign:5

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.010

DANN

Benign

0.46

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.17

T;T

MetaRNN

Benign

0.00077

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.72

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.75

N;N

REVEL

Benign

0.10

Sift

Benign

0.58

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0

B;.

Vest4

0.019

MPC

0.56

ClinPred

0.0051

GERP RS

-7.4

Varity_R

0.036

gMVP

0.49

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