rs763257568

Positions:

• chr19-12663781-G-A

Variant summary

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

The ENST00000456935.7(MAN2B1):​c.685C>T​(p.Arg229Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,052 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MAN2B1 ENST00000456935.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 3.40

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 chr19-12663780-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1479765.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 19-12663781-G-A is Pathogenic according to our data. Variant chr19-12663781-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12663781-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.685C>T	p.Arg229Trp	missense_variant	5/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.685C>T	p.Arg229Trp	missense_variant	5/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.685C>T	p.Arg229Trp	missense_variant	5/24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.685C>T	p.Arg229Trp	missense_variant	5/24	1	NM_000528.4	ENSP00000395473	A1
MAN2B1	ENST00000221363.8	c.685C>T	p.Arg229Trp	missense_variant	5/24	1		ENSP00000221363	P4
MAN2B1	ENST00000486847.2	c.388C>T	p.Arg130Trp	missense_variant	3/4	4		ENSP00000470174
MAN2B1	ENST00000466794.5	n.667C>T		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000159 AC: 4 AN: 251450 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

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: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000187

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

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: 0.0000688 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:6 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2022	Variant summary: MAN2B1 c.685C>T (p.Arg229Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251450 control chromosomes (gnomAD). c.685C>T has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Rise Stensland_2012, Mkaouar_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Berg_2002, Rise Stensland_2012, Mkaouar_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the MAN2B1 protein (p.Arg229Trp). This variant is present in population databases (rs763257568, gnomAD 0.007%). This missense change has been observed in individual(s) with mannosidosis (PMID: 22161967, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208258). 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: 11959458, 22161967). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.685C>T;p.(Arg229Trp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208258; PMID: 26048034; 22161967; 11959458; 21505070) - PS4_moderate.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11959458) - PS3_moderate. The variant is present at low allele frequencies population databases (rs763257568– gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg229Trp) was detected in trans with a Pathogenic variant (PMID: 26048034) - PM3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2022

Published functional studies demonstrate a damaging effect with the presence of the variant resulting in a significant reduction in enzyme activity (Riise Stensland et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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: 11959458, 35871018, 22161967, 21505070, 34614013, 26048034) -

MAN2B1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2024

The MAN2B1 c.685C>T variant is predicted to result in the amino acid substitution p.Arg229Trp. This variant has been reported in the homozygous state or heterozygous state with a second MAN2B1 variant in individuals with alpha-mannosidosis (Riise Stensland et al. 2012. PubMed ID: 22161967; Mkaouar et al. 2021. PubMed ID: 34614013). Functional studies have shown this variant does not impact MANB1 maturation and transportation; however, it was reported to reduce the enzymatic activity to 20-30% of the wildtype enzyme which may correlate with a moderate clinical subtype of the disease (Riise Stensland et al. 2012. PubMed ID: 22161967; Kuokkanen et al. 2011. PubMed ID: 21505070). The intra-familial variability of cognitive impairment has been suggested to be associated with pathogenic variants in other genes (Mkaouar et al. 2021. PubMed ID: 34614013). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.7	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.0	D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.010	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.70		Loss of MoRF binding (P = 0.0387);Loss of MoRF binding (P = 0.0387);.;
MVP		0.94
MPC		1.5
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.96

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

Other links and lift over

dbSNP: rs763257568; hg19: chr19-12774595;