rs75029862

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000528.4(MAN2B1):c.2006C>T(p.Pro669Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,614,086 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 64 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 8.87

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 links:

MAN2B1 (HGNC:):

MAN2B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075194538).

BP6

Variant 19-12652193-G-A is Benign according to our data. Variant chr19-12652193-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 218459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0051 (777/152222) while in subpopulation EAS AF= 0.0406 (210/5178). AF 95% confidence interval is 0.0361. There are 21 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4 linkuse as main transcript	c.2006C>T	p.Pro669Leu	missense_variant	16/24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001173498.2 linkuse as main transcript	c.2003C>T	p.Pro668Leu	missense_variant	16/24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_005259913.3 linkuse as main transcript	c.2009C>T	p.Pro670Leu	missense_variant	16/24		XP_005259970.1
MAN2B1	XM_047438841.1 linkuse as main transcript	c.905C>T	p.Pro302Leu	missense_variant	9/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 linkuse as main transcript	c.2006C>T	p.Pro669Leu	missense_variant	16/24	1	NM_000528.4	ENSP00000395473.2		O00754-1

Frequencies

GnomAD3 genomes

AF:

0.00512

AC:

779

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.0410

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00924

AC:

2324

AN:

251466

Hom.:

AF XY:

0.00791

AC XY:

1075

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0408

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0431

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00259

AC:

3784

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1770

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0407

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.0367

Gnomad4 SAS exome

AF:

0.00104

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.00344

GnomAD4 genome

AF:

0.00510

AC:

777

AN:

152222

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

432

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.0318

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.0406

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.00775

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00767

AC:

931

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2022	See Variant Classification Assertion Criteria. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 08, 2017	Variant summary: The MAN2B1 c.2006C>T (p.Pro669Leu) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2336/277222 (34 homozygotes) control chromosomes (gnomAD) at a frequency of 0.0084265, which is approximately 5 times the estimated maximal expected allele frequency of a pathogenic MAN2B1 variant (0.0015811), suggesting this variant is likely a benign polymorphism. Functional study showed variant with comparable level of activity as wild type (Stensland_015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2016	- -

Deficiency of alpha-mannosidase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Uncertain

0.59

Sift

Benign

0.14

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.99

D;.

Vest4

0.68

MVP

0.89

MPC

0.58

ClinPred

0.032

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over