rs1054487

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000528.4(MAN2B1):c.935C>T(p.Thr312Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,610,788 control chromosomes in the GnomAD database, including 121,803 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. T312N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.41 ( 13848 hom., cov: 32)

Exomes 𝑓: 0.37 ( 107955 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.96

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=1.6364455E-4).

BP6

Variant 19-12661351-G-A is Benign according to our data. Variant chr19-12661351-G-A is described in ClinVar as [Benign]. Clinvar id is 93218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12661351-G-A is described in Lovd as [Benign]. Variant chr19-12661351-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.935C>T	p.Thr312Ile	missense_variant	Exon 7 of 24	ENST00000456935.7	NP_000519.2	O00754-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAN2B1	ENST00000456935.7 link	c.935C>T	p.Thr312Ile	missense_variant	Exon 7 of 24	1	NM_000528.4	ENSP00000395473.2	O00754-1
MAN2B1	ENST00000221363.8 link	c.935C>T	p.Thr312Ile	missense_variant	Exon 7 of 24	1		ENSP00000221363.4	O00754-2
MAN2B1	ENST00000462144.1 link	n.128C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
MAN2B1	ENST00000466794.5 link	n.917C>T		non_coding_transcript_exon_variant	Exon 7 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.410

AC:

62314

AN:

151958

Hom.:

13826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.549

Gnomad AMI

AF:

0.299

Gnomad AMR

AF:

0.293

Gnomad ASJ

AF:

0.519

Gnomad EAS

AF:

0.0544

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.298

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.418

GnomAD3 exomes

AF:

0.332

AC:

83511

AN:

251472

Hom.:

16124

AF XY:

0.333

AC XY:

45309

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.551

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.513

Gnomad EAS exome

AF:

0.0505

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.295

Gnomad NFE exome

AF:

0.399

Gnomad OTH exome

AF:

0.366

GnomAD4 exome

AF:

0.373

AC:

544784

AN:

1458712

Hom.:

107955

Cov.:

AF XY:

0.371

AC XY:

269149

AN XY:

725794

show subpopulations

Gnomad4 AFR exome

AF:

0.557

Gnomad4 AMR exome

AF:

0.218

Gnomad4 ASJ exome

AF:

0.521

Gnomad4 EAS exome

AF:

0.0497

Gnomad4 SAS exome

AF:

0.236

Gnomad4 FIN exome

AF:

0.298

Gnomad4 NFE exome

AF:

0.396

Gnomad4 OTH exome

AF:

0.371

GnomAD4 genome

AF:

0.410

AC:

62360

AN:

152076

Hom.:

13848

Cov.:

AF XY:

0.400

AC XY:

29725

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.549

Gnomad4 AMR

AF:

0.293

Gnomad4 ASJ

AF:

0.519

Gnomad4 EAS

AF:

0.0544

Gnomad4 SAS

AF:

0.227

Gnomad4 FIN

AF:

0.298

Gnomad4 NFE

AF:

0.405

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.395

Hom.:

26087

Bravo

AF:

0.418

TwinsUK

AF:

0.392

AC:

1454

ALSPAC

AF:

0.396

AC:

1527

ESP6500AA

AF:

0.537

AC:

2366

ESP6500EA

AF:

0.411

AC:

3533

ExAC

AF:

0.340

AC:

41261

EpiCase

AF:

0.418

EpiControl

AF:

0.409

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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 -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Apr 24, 2015

Eurofins Ntd Llc (ga)

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

- -

Nov 07, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MAN2B1 c.935C>T (p.Thr312Ile) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 94194/277144 control (gnomAD) chromosomes (18497 homozygotes) at a frequency of 0.3398739, which is approximately 215 times the estimated maximal expected allele frequency of a pathogenic MAN2B1 variant (0.0015811), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Deficiency of alpha-mannosidase

Benign:5

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

- -

Jan 13, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.35

DANN

Benign

0.13

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.00016

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.8

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

2.6

N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;.

Vest4

0.072

MPC

0.61

ClinPred

0.0065

GERP RS

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.35

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