19-12661276-C-T

Variant names:

• chr19-12661276-C-T
• rs1133330
• NM_000528.4:c.1010G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000528.4(MAN2B1):​c.1010G>A​(p.Arg337Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,609,782 control chromosomes in the GnomAD database, including 108,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9273 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98881 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0290
• Publications: 50 publications found

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 Gene-Disease associations (from GenCC):

• alpha-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-12661276-C-T is Benign according to our data. Variant chr19-12661276-C-T is described in ClinVar as Benign. ClinVar VariationId is 93207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.1010G>A	p.Arg337Gln	missense_variant	Exon 7 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001440570.1	c.1010G>A	p.Arg337Gln	missense_variant	Exon 7 of 24		NP_001427499.1
MAN2B1	NM_001173498.2	c.1010G>A	p.Arg337Gln	missense_variant	Exon 7 of 24		NP_001166969.1
MAN2B1	XM_047438841.1	c.-9G>A		5_prime_UTR_variant	Exon 1 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.1010G>A	p.Arg337Gln	missense_variant	Exon 7 of 24	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.9	c.1010G>A	p.Arg337Gln	missense_variant	Exon 7 of 24	1		ENSP00000221363.4
MAN2B1	ENST00000462144.1	n.203G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
MAN2B1	ENST00000466794.5	n.992G>A		non_coding_transcript_exon_variant	Exon 7 of 22	2

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51559 AN: 151944 Hom.: 9270 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.0549

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.307 AC: 77077 AN: 251434 AF XY: 0.312

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.358 AC: 522125 AN: 1457720 Hom.: 98881 Cov.: 32 AF XY: 0.357 AC XY: 258625 AN XY: 725386

African (AFR) AF: 0.322 AC: 10748 AN: 33394

American (AMR) AF: 0.199 AC: 8877 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12814 AN: 26082

East Asian (EAS) AF: 0.0497 AC: 1973 AN: 39686

South Asian (SAS) AF: 0.231 AC: 19920 AN: 86198

European-Finnish (FIN) AF: 0.291 AC: 15511 AN: 53380

Middle Eastern (MID) AF: 0.432 AC: 2477 AN: 5734

European-Non Finnish (NFE) AF: 0.387 AC: 429024 AN: 1108308

Other (OTH) AF: 0.345 AC: 20781 AN: 60236

GnomAD4 genome AF: 0.339 AC: 51573 AN: 152062 Hom.: 9273 Cov.: 32 AF XY: 0.331 AC XY: 24624 AN XY: 74312

African (AFR) AF: 0.324 AC: 13441 AN: 41466

American (AMR) AF: 0.261 AC: 3980 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1694 AN: 3470

East Asian (EAS) AF: 0.0549 AC: 284 AN: 5176

South Asian (SAS) AF: 0.223 AC: 1077 AN: 4830

European-Finnish (FIN) AF: 0.291 AC: 3077 AN: 10556

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26869 AN: 67968

Other (OTH) AF: 0.357 AC: 754 AN: 2112

Alfa AF: 0.373 Hom.: 55127

Bravo AF: 0.335

TwinsUK AF: 0.384 AC: 1424

ALSPAC AF: 0.389 AC: 1499

ESP6500AA AF: 0.313 AC: 1379

ESP6500EA AF: 0.399 AC: 3431

ExAC AF: 0.310 AC: 37687

Asia WGS AF: 0.158 AC: 551 AN: 3478

EpiCase AF: 0.407

EpiControl AF: 0.396

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, ClinVar assertions are B/LB

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 07, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MAN2B1 c.1010G>A (p.Arg337Gln) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 85845/277142 control chromosomes (30 homozygotes) at a frequency of 0.309751, which is approximately 196 times the estimated maximal expected allele frequency of a pathogenic MAN2B1 variant (0.0015811), suggesting this variant is likely a benign polymorphism. This variant has been reported in affected individuals co-occuring with pathogenic mutations and is listed as polymorphism by authors (Sbaragli_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Deficiency of alpha-mannosidase Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.00050	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N;N
PhyloP100		-0.029
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.22
Sift	Benign	0.33	T;T
Sift4G	Benign	0.23	T;T
Vest4		0.032
ClinPred		0.0077	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1133330; hg19: chr19-12772090; COSMIC: COSV55471603; COSMIC: COSV55471603;