rs80338680

chr19-12649932-G-Achr19-12649932-G-Cchr19-12649932-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000528.4(MAN2B1):c.2248C>T(p.Arg750Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,602,428 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R750Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1 O:1
• Conservation: PhyloP100: 2.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12649932-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1498522.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 19-12649932-G-A is Pathogenic according to our data. Variant chr19-12649932-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12649932-G-A is described in Lovd as [Pathogenic]. Variant chr19-12649932-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.2248C>T	p.Arg750Trp	missense_variant	18/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.2245C>T	p.Arg749Trp	missense_variant	18/24
MAN2B1	XM_005259913.3	c.2251C>T	p.Arg751Trp	missense_variant	18/24
MAN2B1	XM_047438841.1	c.1147C>T	p.Arg383Trp	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2248C>T	p.Arg750Trp	missense_variant	18/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.2245C>T	p.Arg749Trp	missense_variant	18/24	1		P4
MAN2B1	ENST00000466794.5	n.2838C>T		non_coding_transcript_exon_variant	16/22	2

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 45 AN: 144416 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000704

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000422

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251482 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135916

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000158 AC: 230 AN: 1457926 Hom.: 0 Cov.: 34 AF XY: 0.000160 AC XY: 116 AN XY: 725240

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000677

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.000311 AC: 45 AN: 144502 Hom.: 0 Cov.: 30 AF XY: 0.000343 AC XY: 24 AN XY: 70014

Gnomad4 AFR AF: 0.000104

Gnomad4 AMR AF: 0.0000703

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000216

Gnomad4 FIN AF: 0.00118

Gnomad4 NFE AF: 0.000422

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:15 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000528.3(MAN2B1):c.2248C>T(R750W) is classified as pathogenic in the context of alpha-mannosidosis. Sources cited for classification include the following: PMID 22161967, 9915946, 23613340, 9758606 and 15035660. Classification of NM_000528.3(MAN2B1):c.2248C>T(R750W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 16, 2017	The MAN2B1 c.2248C>T (p.Arg750Trp) missense variant is one of the most frequently reported variants among individuals with alpha-mannosidosis from European populations and generally accounts for more than 27% of all disease alleles in studied cohorts (Malm et al. 2001; Riise Stensland et al. 2012; Borgwardt et al. 2015). Across a selection of the available literature, the p.Arg750Trp variant has been identified in at least 50 individuals with alpha-mannosidosis, including 22 individuals in a homozygous state and 28 individuals in a compound heterozygous state (Gotoda et al. 1998; Berg et al. 1999; Riise Stensland et al. 2012; Borgwardt et al. 2015). The p.Arg750Trp variant was absent from at least 236 control alleles but is reported at a frequency of 0.001361 in the European (Finnish) population of the Exome Aggregation Consortium. The activity of alpha mannosidase in fibroblasts of two unrelated patients has been reported to demonstrate two percent activity of normal (Gotoda et al. 1998). Nearly absent enzyme activity due to misfolded protein arrested in the endoplasmic reticulum as inactive single-chain forms has been demonstrated in COS1 and COS7 cells transfected with the p.Arg750Trp variant (Gotoda et al. 1998; Hansen et al. 2004). The p.Arg750Trp variant has been used as a negative control for functional analysis of novel MAN2B1 variants (Borgwardt et al. 2015). Based on the collective evidence, the p.Arg750Trp variant is classified as pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 30, 2019	This variant was identified as homozygous -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 19, 2020	The p.Arg750Trp variant in MAN2B1 has been reported in the homozygous or compound heterozygous state in >50 individuals with alpha-mannosidosis and segregated with disease in at least 5 affected individuals from 5 families (Berg 1999 PMID: 9915946, Lehalle 2019 PMID: 31241255, Gotoda 1998 PMID: 9758606, Riise Stensland 2012 PMID: 22161967, Gotoda 1998 PMID: 9758606). It has also been identified in 0.12% (29/25036) of Finnish chromosomes and 0.04% (48/128844) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg750Trp variant has also been reported in ClinVar (Variation ID 1687). Computational prediction tools and conservation analyses are consistent with pathogenicity. In vitro functional studies support that this variant impacts protein function (Hansen 2004 PMID: 15035660, Khan 2009 PMID: 19958498). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha-mannosidosis. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PP3, PS3_Supporting. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 750 of the MAN2B1 protein (p.Arg750Trp). This variant is present in population databases (rs80338680, gnomAD 0.1%). This missense change has been observed in individuals with MAN2B1-related conditions (PMID: 9758606, 9915946, 22161967). ClinVar contains an entry for this variant (Variation ID: 1687). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 9758606, 15035660). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 29, 2023	PS3, PM2, PM3_Very Strong, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with types I and II alpha-mannosidosis (MIM#248500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 83 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 6 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolases family 38 C-terminal domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants reported in individuals with alpha-mannosidosis (ClinVar, PMID: 26048034). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2017	Variant summary: The MAN2B1 c.2248C>T (p.Arg750Trp) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 28/121552 control chromosomes at a frequency of 0.0002304, which does not exceed the estimated maximal expected allele frequency of a pathogenic MAN2B1 variant (0.0015811). The variant has been reported in numerous affected individuals in the literature, both in the homozgyous and compound heterozygous state. Additionally, a functional study showed that the variant protein was misfolded and arrested in the ER as inactive single-chain form, and patients and transfected cell lines both had almost no detectable enzyme activity (Gotoda_1998, Hansen_2004). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MAN2B1: PM3:Very Strong, PM2, PP4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2022	Published functional studies demonstrate that R750W impairs enzyme activity and is damaging to protein function in vitro (Gotoda et al., 1998; Hansen et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19958498, 18651971, 16919251, 15035660, 9758606, 26048034, 9915946, 34426522, 31589614, 31241255, 30548430, 31980526, 22161967) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MVP		0.92
MPC		0.89
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.80
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs80338680; hg19: chr19-12760746; COSMIC: COSV55470688; COSMIC: COSV55470688;