19-12649146-A-G

Position:

• chr19-12649146-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000528.4(MAN2B1):​c.2426T>C​(p.Leu809Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000887 in 1,612,018 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 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1 O:1
• Conservation: PhyloP100: 8.79

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 19-12649146-A-G is Pathogenic according to our data. Variant chr19-12649146-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12649146-A-G is described in Lovd as [Pathogenic]. Variant chr19-12649146-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2426T>C	p.Leu809Pro	missense_variant	20/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.2423T>C	p.Leu808Pro	missense_variant	20/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.2429T>C	p.Leu810Pro	missense_variant	20/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.1325T>C	p.Leu442Pro	missense_variant	13/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2426T>C	p.Leu809Pro	missense_variant	20/24	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.8	c.2423T>C	p.Leu808Pro	missense_variant	20/24	1		ENSP00000221363.4
MAN2B1	ENST00000466794.5	n.3016T>C		non_coding_transcript_exon_variant	18/22	2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251186 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135786

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: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000925 AC: 135 AN: 1459862 Hom.: 0 Cov.: 33 AF XY: 0.0000909 AC XY: 66 AN XY: 726240

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: 0.000120

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74322

Gnomad4 AFR AF: 0.0000483

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: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:11 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2018	Variant summary: MAN2B1 c.2426T>C (p.Leu809Pro) results in a non-conservative amino acid change located in the glycosyl hydrolase family-38 C-terminal domain (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 6.9e-05 in 277176 control chromosomes (gnomAD and publication controls). This frequency is not higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (6.9e-05 vs 0.0016), allowing no conclusion about variant significance. The variant, c.2426T>C, has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Berg 1999, Borgwardt 2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <10% of normal activity (Berg 1999, Hansen 2004). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 02, 2022	PM3_Strong, PS3, PP3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 809 of the MAN2B1 protein (p.Leu809Pro). This variant is present in population databases (rs80338681, gnomAD 0.01%). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 9915946, 22161967, 23613340, 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: 21210). 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: 9915946, 15035660). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Dec 15, 2023	This sequence variant is a single nucleotide substitution (T>C) at position 2426 of the coding sequence of the MAN2B1 gene that results in a leucine to proline amino acid change at residue 809 of the mannosidase alpha class 2B member 1 protein. This is a previously reported variant (ClinVar 21210) that has been observed in homozygous and compound heterozygous individuals affected by alpha-mannosidosis (PMID: 22161967, 9915946, 15035660, 26048034). This variant is present in 25 of 403342 alleles (0.0062%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this Leu to Pro amino acid change would be damaging, and the Leu809 residue at this position is highly conserved across the vertebrate species examined. The activity of the variant protein is significantly reduced when expressed in cultured fibroblasts and COS cells (PMID: 9915946, 15035660). This is likely due to the misfolding of the protein resulting its retention in the endoplasmic reticulum (PMID: 15035660, 26048034). Given this information, we consider this a likely pathogenic variant. ACMG Criteria: PM3, PP3, PS3 -
Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 07, 2012	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2022	- -

MAN2B1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2024

The MAN2B1 c.2426T>C variant is predicted to result in the amino acid substitution p.Leu809Pro. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with alpha-mannosidosis (see for example Berg. et al. 1999. PubMed ID: 9915946; Borgwardt. et al. 2015. PubMed ID: 26048034). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is interpreted as pathogenic in ClinVar by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/21210/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.97
MVP		0.98
MPC		1.1
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.97

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

Other links and lift over

dbSNP: rs80338681; hg19: chr19-12759960;