rs142702682

Positions:

• chr19-12649171-C-A
• chr19-12649171-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM5 PP3_Moderate BS2

The NM_000528.4(MAN2B1):​c.2401G>T​(p.Gly801Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,612,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G801D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 7.47

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 Uncertain_significance. Variant got 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12649170-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2401G>T	p.Gly801Cys	missense_variant	20/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.2398G>T	p.Gly800Cys	missense_variant	20/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.2404G>T	p.Gly802Cys	missense_variant	20/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.1300G>T	p.Gly434Cys	missense_variant	13/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2401G>T	p.Gly801Cys	missense_variant	20/24	1	NM_000528.4	ENSP00000395473	A1
MAN2B1	ENST00000221363.8	c.2398G>T	p.Gly800Cys	missense_variant	20/24	1		ENSP00000221363	P4
MAN2B1	ENST00000466794.5	n.2991G>T		non_coding_transcript_exon_variant	18/22	2

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000465 AC: 117 AN: 251382 Hom.: 1 AF XY: 0.000449 AC XY: 61 AN XY: 135884

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000390 AC: 570 AN: 1460412 Hom.: 2 Cov.: 33 AF XY: 0.000376 AC XY: 273 AN XY: 726510

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.000393

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152246 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22 AN XY: 74448

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 801 of the MAN2B1 protein (p.Gly801Cys). This variant is present in population databases (rs142702682, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547954). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2021

The c.2401G>T (p.G801C) alteration is located in exon 20 (coding exon 20) of the MAN2B1 gene. This alteration results from a G to T substitution at nucleotide position 2401, causing the glycine (G) at amino acid position 801 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MAN2B1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2023

The MAN2B1 c.2401G>T variant is predicted to result in the amino acid substitution p.Gly801Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/19-12759985-C-A), which may be too common to be causative. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.86
MVP		0.97
MPC		0.89
ClinPred		0.31	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.86

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: rs142702682; hg19: chr19-12759985;