rs2866413

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005908.4(MANBA):c.2102C>T(p.Thr701Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,608,224 control chromosomes in the GnomAD database, including 223,306 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. T701R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.55 ( 23376 hom., cov: 33)

Exomes 𝑓: 0.52 ( 199930 hom. )

Consequence

MANBA
NM_005908.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.82

Publications

76 publications found

Variant links:

Genes affected

MANBA (HGNC:6831): (mannosidase beta) This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

MANBA Gene-Disease associations (from GenCC):

beta-mannosidosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics

MANBA 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=4.2311553E-6).

BP6

Variant 4-102635920-G-A is Benign according to our data. Variant chr4-102635920-G-A is described in ClinVar as [Benign]. Clinvar id is 95319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4 link	c.2102C>T	p.Thr701Met	missense_variant	Exon 15 of 17	ENST00000647097.2	NP_005899.3	O00462
MANBA	XM_047415692.1 link	c.2027C>T	p.Thr676Met	missense_variant	Exon 16 of 18		XP_047271648.1
MANBA	XM_047415693.1 link	c.2027C>T	p.Thr676Met	missense_variant	Exon 16 of 18		XP_047271649.1
MANBA	XM_047415694.1 link	c.1454C>T	p.Thr485Met	missense_variant	Exon 11 of 13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2 link	c.2102C>T	p.Thr701Met	missense_variant	Exon 15 of 17		NM_005908.4	ENSP00000495247.1		O00462

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83451

AN:

151906

Hom.:

23342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.575

Gnomad AMR

AF:

0.618

Gnomad ASJ

AF:

0.508

Gnomad EAS

AF:

0.515

Gnomad SAS

AF:

0.452

Gnomad FIN

AF:

0.472

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.556

GnomAD2 exomes

AF:

0.541

AC:

135812

AN:

251266

AF XY:

0.529

show subpopulations

Gnomad AFR exome

AF:

0.635

Gnomad AMR exome

AF:

0.735

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.527

Gnomad FIN exome

AF:

0.487

Gnomad NFE exome

AF:

0.508

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.521

AC:

758213

AN:

1456200

Hom.:

199930

Cov.:

AF XY:

0.517

AC XY:

375007

AN XY:

724730

show subpopulations

African (AFR)

AF:

0.634

AC:

21111

AN:

33322

American (AMR)

AF:

0.724

AC:

32371

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.493

AC:

12862

AN:

26108

East Asian (EAS)

AF:

0.491

AC:

19471

AN:

39670

South Asian (SAS)

AF:

0.461

AC:

39724

AN:

86138

European-Finnish (FIN)

AF:

0.476

AC:

25410

AN:

53380

Middle Eastern (MID)

AF:

0.568

AC:

3268

AN:

5752

European-Non Finnish (NFE)

AF:

0.517

AC:

571975

AN:

1106902

Other (OTH)

AF:

0.532

AC:

32021

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

18691

37383

56074

74766

93457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.549

AC:

83529

AN:

152024

Hom.:

23376

Cov.:

AF XY:

0.548

AC XY:

40747

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.630

AC:

26125

AN:

41438

American (AMR)

AF:

0.618

AC:

9445

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.508

AC:

1765

AN:

3472

East Asian (EAS)

AF:

0.515

AC:

2671

AN:

5182

South Asian (SAS)

AF:

0.452

AC:

2178

AN:

4822

European-Finnish (FIN)

AF:

0.472

AC:

4975

AN:

10548

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.508

AC:

34512

AN:

67970

Other (OTH)

AF:

0.549

AC:

1156

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1924

3849

5773

7698

9622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.520

Hom.:

97638

Bravo

AF:

0.567

TwinsUK

AF:

0.513

AC:

1903

ALSPAC

AF:

0.520

AC:

2005

ESP6500AA

AF:

0.617

AC:

2720

ESP6500EA

AF:

0.513

AC:

4413

ExAC

AF:

0.533

AC:

64658

Asia WGS

AF:

0.503

AC:

1744

AN:

3478

EpiCase

AF:

0.515

EpiControl

AF:

0.504

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 21, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 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 -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Beta-D-mannosidosis

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.5

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.26

.;T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.39

T;.;T;T;T

MetaRNN

Benign

0.0000042

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.030

.;N;N;.;.

PhyloP100

1.8

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.48

.;N;.;.;N

REVEL

Benign

0.042

Sift

Benign

0.17

.;T;.;.;T

Sift4G

Benign

0.12

.;T;.;.;T

Polyphen

0.060, 0.054

.;B;B;.;B

Vest4

0.066, 0.030

MPC

0.078

ClinPred

0.010

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.34

Mutation Taster

=100/0

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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rs2866413

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