rs61234887

Positions:

chr19-12649959-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000528.4(MAN2B1):c.2221G>A(p.Gly741Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,613,858 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 78 hom., cov: 30)

Exomes 𝑓: 0.0018 ( 62 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.40

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004482478).

BP6

Variant 19-12649959-C-T is Benign according to our data. Variant chr19-12649959-C-T is described in ClinVar as [Benign]. Clinvar id is 235571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12649959-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAN2B1	NM_000528.4 linkuse as main transcript	c.2221G>A	p.Gly741Arg	missense_variant	18/24	ENST00000456935.7
MAN2B1	NM_001173498.2 linkuse as main transcript	c.2218G>A	p.Gly740Arg	missense_variant	18/24
MAN2B1	XM_005259913.3 linkuse as main transcript	c.2224G>A	p.Gly742Arg	missense_variant	18/24
MAN2B1	XM_047438841.1 linkuse as main transcript	c.1120G>A	p.Gly374Arg	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7 linkuse as main transcript	c.2221G>A	p.Gly741Arg	missense_variant	18/24	1	NM_000528.4	A1	O00754-1
MAN2B1	ENST00000221363.8 linkuse as main transcript	c.2218G>A	p.Gly740Arg	missense_variant	18/24	1		P4	O00754-2
MAN2B1	ENST00000466794.5 linkuse as main transcript	n.2811G>A		non_coding_transcript_exon_variant	16/22	2

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2546

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0574

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00866

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0140

GnomAD3 exomes

AF:

0.00433

AC:

1088

AN:

251496

Hom.:

AF XY:

0.00318

AC XY:

432

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0565

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00178

AC:

2598

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1099

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0594

Gnomad4 AMR exome

AF:

0.00371

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000136

Gnomad4 OTH exome

AF:

0.00439

GnomAD4 genome

AF:

0.0168

AC:

2556

AN:

151986

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1189

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0574

Gnomad4 AMR

AF:

0.00865

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.0138

Alfa

AF:

0.00303

Hom.:

Bravo

AF:

0.0193

ESP6500AA

AF:

0.0574

AC:

253

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00516

AC:

627

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2015	- -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0045

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.60

MutPred

0.63

Loss of ubiquitination at K740 (P = 0.0255);.;

MVP

0.92

MPC

0.90

ClinPred

0.035

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.67

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

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