19-12661351-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 Likely 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

Publications

49 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: Benign. The variant received -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 VariationId is 93218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	ENST00000221363.9 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

GnomAD2 exomes

AF:

0.332

AC:

83511

AN:

251472

AF XY:

0.333

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 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

African (AFR)

AF:

0.557

AC:

18626

AN:

33412

American (AMR)

AF:

0.218

AC:

9758

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

13594

AN:

26100

East Asian (EAS)

AF:

0.0497

AC:

1971

AN:

39684

South Asian (SAS)

AF:

0.236

AC:

20357

AN:

86216

European-Finnish (FIN)

AF:

0.298

AC:

15902

AN:

53384

Middle Eastern (MID)

AF:

0.465

AC:

2673

AN:

5750

European-Non Finnish (NFE)

AF:

0.396

AC:

439558

AN:

1109174

Other (OTH)

AF:

0.371

AC:

22345

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

18172

36344

54515

72687

90859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13336

26672

40008

53344

66680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.410

AC:

62360

AN:

152076

Hom.:

13848

Cov.:

AF XY:

0.400

AC XY:

29725

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.549

AC:

22782

AN:

41474

American (AMR)

AF:

0.293

AC:

4473

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.519

AC:

1803

AN:

3472

East Asian (EAS)

AF:

0.0544

AC:

281

AN:

5168

South Asian (SAS)

AF:

0.227

AC:

1095

AN:

4830

European-Finnish (FIN)

AF:

0.298

AC:

3147

AN:

10566

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.405

AC:

27495

AN:

67970

Other (OTH)

AF:

0.415

AC:

874

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1829

3658

5488

7317

9146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.400

Hom.:

38013

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

- -

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

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. -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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. -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.0

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over