rs34544747

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.1441G>T(p.Ala481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,611,712 control chromosomes in the GnomAD database, including 1,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A481A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.067 ( 880 hom., cov: 32)

Exomes 𝑓: 0.019 ( 976 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.73

Publications

15 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=0.0021640658).

BP6

Variant 19-12657035-C-A is Benign according to our data. Variant chr19-12657035-C-A is described in ClinVar as [Benign]. Clinvar id is 93210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.1441G>T	p.Ala481Ser	missense_variant	Exon 12 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.1444G>T	p.Ala482Ser	missense_variant	Exon 12 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.1438G>T	p.Ala480Ser	missense_variant	Exon 12 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_047438841.1 link	c.340G>T	p.Ala114Ser	missense_variant	Exon 5 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.1441G>T	p.Ala481Ser	missense_variant	Exon 12 of 24	1	NM_000528.4	ENSP00000395473.2		O00754-1

Frequencies

GnomAD3 genomes

AF:

0.0671

AC:

10209

AN:

152148

Hom.:

878

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0393

Gnomad ASJ

AF:

0.0680

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00682

Gnomad FIN

AF:

0.000564

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.0650

GnomAD2 exomes

AF:

0.0262

AC:

6482

AN:

247852

AF XY:

0.0225

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0644

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.0193

AC:

28198

AN:

1459446

Hom.:

976

Cov.:

AF XY:

0.0185

AC XY:

13467

AN XY:

726046

show subpopulations

African (AFR)

AF:

0.204

AC:

6804

AN:

33422

American (AMR)

AF:

0.0227

AC:

1012

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.0650

AC:

1698

AN:

26110

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.00452

AC:

389

AN:

86084

European-Finnish (FIN)

AF:

0.00115

AC:

AN:

52058

Middle Eastern (MID)

AF:

0.0451

AC:

260

AN:

5764

European-Non Finnish (NFE)

AF:

0.0145

AC:

16166

AN:

1111338

Other (OTH)

AF:

0.0299

AC:

1807

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1443

2887

4330

5774

7217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0672

AC:

10229

AN:

152266

Hom.:

880

Cov.:

AF XY:

0.0648

AC XY:

4825

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.197

AC:

8173

AN:

41524

American (AMR)

AF:

0.0391

AC:

599

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0680

AC:

236

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00641

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000564

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0145

AC:

985

AN:

68016

Other (OTH)

AF:

0.0643

AC:

136

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

417

833

1250

1666

2083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0301

Hom.:

958

Bravo

AF:

0.0766

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.184

AC:

809

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0286

AC:

3467

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0175

EpiControl

AF:

0.0184

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely 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

- -

Jun 07, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Deficiency of alpha-mannosidase

Benign:4

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 05, 2012

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

T;.

Eigen

Benign

-0.054

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

1.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.58

N;N

REVEL

Benign

0.23

Sift

Benign

0.59

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.37

B;.

Vest4

0.11

MPC

0.52

ClinPred

0.013

GERP RS

4.2

Varity_R

0.076

gMVP

0.53

Mutation Taster

=97/3

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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rs34544747

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