19-12665743-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000528.4(MAN2B1):c.222C>A(p.Asp74Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: -0.150

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:

ENSG00000269590 (HGNC:):

ENSG00000269590 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 19-12665743-G-T is Pathogenic according to our data. Variant chr19-12665743-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12665743-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.222C>A	p.Asp74Glu	missense_variant	Exon 2 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001173498.2 link	c.222C>A	p.Asp74Glu	missense_variant	Exon 2 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_005259913.3 link	c.222C>A	p.Asp74Glu	missense_variant	Exon 2 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.222C>A	p.Asp74Glu	missense_variant	Exon 2 of 24	1	NM_000528.4	ENSP00000395473.2		O00754-1
ENSG00000269590	ENST00000597961.1 link	c.213C>A	p.Asp71Glu	missense_variant	Exon 3 of 5	4		ENSP00000472710.1		M0R2P5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251462

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000648

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Pathogenic:2Uncertain:1

Jan 06, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAN2B1 c.222C>A (p.Asp74Glu) results in a conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251662 control chromosomes (gnomAD and publication data). c.222C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis or suspected mitochondrial disorders (Riise Stensland_2012, Lieber_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies reported this variant has dramatically reduced alpha-mannosidase activity in transfected cells and was both proteolytically processed and extracellularly secreted, but less efficiently than the wild-type (Kuokkanen_2011, Riise Stensland_2012, Riise Stensland_2015). One ClinVar submitter (evaluation after 2014) cites this variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 07, 2012

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Mar 11, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (absent alpha-mannosidase activity) (PMID: 22161967); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21505070, Mandl2024[Computational], 31775018, 38107468, 39976451, 22161967) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.8

H;H;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

D;D;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.96

MutPred

0.93

Gain of ubiquitination at K79 (P = 0.2122);Gain of ubiquitination at K79 (P = 0.2122);.;.;

MVP

0.93

MPC

1.5

ClinPred

1.0

GERP RS

-3.8

Varity_R

0.91

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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