rs117843968

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000528.4(MAN2B1):c.743C>T(p.Pro248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,612,812 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 27 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 7.35

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03565052).

BP6

Variant 19-12663723-G-A is Benign according to our data. Variant chr19-12663723-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197684.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr19-12663723-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00234 (356/152292) while in subpopulation NFE AF= 0.00406 (276/67998). AF 95% confidence interval is 0.00367. There are 1 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAN2B1	NM_000528.4 linkuse as main transcript	c.743C>T	p.Pro248Leu	missense_variant	5/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2 linkuse as main transcript	c.743C>T	p.Pro248Leu	missense_variant	5/24		NP_001166969.1
MAN2B1	XM_005259913.3 linkuse as main transcript	c.743C>T	p.Pro248Leu	missense_variant	5/24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 linkuse as main transcript	c.743C>T	p.Pro248Leu	missense_variant	5/24	1	NM_000528.4	ENSP00000395473	A1	O00754-1
MAN2B1	ENST00000221363.8 linkuse as main transcript	c.743C>T	p.Pro248Leu	missense_variant	5/24	1		ENSP00000221363	P4	O00754-2
MAN2B1	ENST00000486847.2 linkuse as main transcript	c.446C>T	p.Pro149Leu	missense_variant	3/4	4		ENSP00000470174
MAN2B1	ENST00000466794.5 linkuse as main transcript	n.725C>T		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

356

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00230

AC:

570

AN:

247534

Hom.:

AF XY:

0.00241

AC XY:

324

AN XY:

134258

show subpopulations

Gnomad AFR exome

AF:

0.000693

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.00138

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00330

GnomAD4 exome

AF:

0.00455

AC:

6646

AN:

1460520

Hom.:

Cov.:

AF XY:

0.00444

AC XY:

3224

AN XY:

726580

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00186

Gnomad4 FIN exome

AF:

0.00117

Gnomad4 NFE exome

AF:

0.00548

Gnomad4 OTH exome

AF:

0.00380

GnomAD4 genome

AF:

0.00234

AC:

356

AN:

152292

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00406

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.00257

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00235

AC:

285

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2017	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MAN2B1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 30, 2015

- -

MAN2B1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.036

T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.5

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.1

D;D;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.010

D;D;.

Sift4G

Uncertain

0.013

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.45

MVP

0.94

MPC

1.5

ClinPred

0.023

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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