19-12658134-T-C

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.1238A>G(p.Asn413Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,340 control chromosomes in the GnomAD database, including 10,669 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. N413N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.086 ( 850 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9819 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.04

Publications

25 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=0.0019977689).

BP6

Variant 19-12658134-T-C is Benign according to our data. Variant chr19-12658134-T-C is described in ClinVar as Benign. ClinVar VariationId is 129584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.1238A>G	p.Asn413Ser	missense_variant	Exon 10 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.1241A>G	p.Asn414Ser	missense_variant	Exon 10 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.1235A>G	p.Asn412Ser	missense_variant	Exon 10 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_047438841.1 link	c.137A>G	p.Asn46Ser	missense_variant	Exon 3 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.1238A>G	p.Asn413Ser	missense_variant	Exon 10 of 24	1	NM_000528.4	ENSP00000395473.2		O00754-1

Frequencies

GnomAD3 genomes

AF:

0.0865

AC:

13147

AN:

151994

Hom.:

850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.213

Gnomad AMR

AF:

0.0570

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.0804

GnomAD2 exomes

AF:

0.0901

AC:

22434

AN:

249038

AF XY:

0.0897

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.0440

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.108

AC:

157991

AN:

1461228

Hom.:

9819

Cov.:

AF XY:

0.106

AC XY:

77266

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.0167

AC:

560

AN:

33478

American (AMR)

AF:

0.0460

AC:

2056

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3237

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0229

AC:

1973

AN:

86256

European-Finnish (FIN)

AF:

0.196

AC:

10384

AN:

52870

Middle Eastern (MID)

AF:

0.0497

AC:

286

AN:

5756

European-Non Finnish (NFE)

AF:

0.120

AC:

133578

AN:

1111928

Other (OTH)

AF:

0.0979

AC:

5914

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

8144

16288

24433

32577

40721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4646

9292

13938

18584

23230

<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:

0.0864

AC:

13149

AN:

152112

Hom.:

850

Cov.:

AF XY:

0.0875

AC XY:

6502

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0211

AC:

875

AN:

41524

American (AMR)

AF:

0.0569

AC:

870

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

436

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0214

AC:

103

AN:

4820

European-Finnish (FIN)

AF:

0.205

AC:

2169

AN:

10578

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8319

AN:

67942

Other (OTH)

AF:

0.0791

AC:

167

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

594

1189

1783

2378

2972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.101

Hom.:

1583

Bravo

AF:

0.0743

TwinsUK

AF:

0.119

AC:

441

ALSPAC

AF:

0.115

AC:

443

ESP6500AA

AF:

0.0200

AC:

ESP6500EA

AF:

0.120

AC:

1034

ExAC

AF:

0.0897

AC:

10892

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.112

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Benign:4

Jun 10, 2021

Genome-Nilou Lab

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

- -

Nov 22, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

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 09, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

2.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.20

Sift

Benign

0.044

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

0.0050

B;.

Vest4

0.11

MPC

0.48

ClinPred

0.012

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.51

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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