rs61234887

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.2221G>A(p.Gly741Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,613,858 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 78 hom., cov: 30)

Exomes 𝑓: 0.0018 ( 62 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.40

Publications

7 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=0.004482478).

BP6

Variant 19-12649959-C-T is Benign according to our data. Variant chr19-12649959-C-T is described in ClinVar as Benign. ClinVar VariationId is 235571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.2221G>A	p.Gly741Arg	missense_variant	Exon 18 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.2224G>A	p.Gly742Arg	missense_variant	Exon 18 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.2218G>A	p.Gly740Arg	missense_variant	Exon 18 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_047438841.1 link	c.1120G>A	p.Gly374Arg	missense_variant	Exon 11 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAN2B1	ENST00000456935.7 link	c.2221G>A	p.Gly741Arg	missense_variant	Exon 18 of 24	1	NM_000528.4	ENSP00000395473.2	O00754-1
MAN2B1	ENST00000221363.9 link	c.2218G>A	p.Gly740Arg	missense_variant	Exon 18 of 24	1		ENSP00000221363.4	O00754-2
MAN2B1	ENST00000466794.5 link	n.2811G>A		non_coding_transcript_exon_variant	Exon 16 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2546

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0574

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00866

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0140

GnomAD2 exomes

AF:

0.00433

AC:

1088

AN:

251496

AF XY:

0.00318

show subpopulations

Gnomad AFR exome

AF:

0.0565

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00178

AC:

2598

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1099

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0594

AC:

1989

AN:

33478

American (AMR)

AF:

0.00371

AC:

166

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1112004

Other (OTH)

AF:

0.00439

AC:

265

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0168

AC:

2556

AN:

151986

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1189

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0574

AC:

2377

AN:

41390

American (AMR)

AF:

0.00865

AC:

132

AN:

15262

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:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67978

Other (OTH)

AF:

0.0138

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00666

Hom.:

Bravo

AF:

0.0193

ESP6500AA

AF:

0.0574

AC:

253

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00516

AC:

627

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 28, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Deficiency of alpha-mannosidase

Benign:3

Aug 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0045

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.9

M;.

PhyloP100

5.4

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.60

MutPred

0.63

Loss of ubiquitination at K740 (P = 0.0255);.;

MVP

0.92

MPC

0.90

ClinPred

0.035

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.67

Mutation Taster

=84/16

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