rs1054486

chr19-12663394-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000528.4(MAN2B1):c.832C>G(p.Leu278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,613,786 control chromosomes in the GnomAD database, including 65,081 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7350 hom., cov: 31)
  • Exomes 𝑓: 0.27 (57731 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.440

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.7047944E-4).
• BP6: Variant 19-12663394-G-C is Benign according to our data. Variant chr19-12663394-G-C is described in ClinVar as [Benign]. Clinvar id is 93217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12663394-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.832C>G	p.Leu278Val	missense_variant	6/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.832C>G	p.Leu278Val	missense_variant	6/24
MAN2B1	XM_005259913.3	c.832C>G	p.Leu278Val	missense_variant	6/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.832C>G	p.Leu278Val	missense_variant	6/24	1	NM_000528.4	A1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45332 AN: 151826 Hom.: 7348 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.266

GnomAD3 exomes AF: 0.251 AC: 62983 AN: 251424 Hom.: 9032 AF XY: 0.252 AC XY: 34233 AN XY: 135888

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.295

Gnomad EAS exome AF: 0.0307

Gnomad SAS exome AF: 0.180

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.274 AC: 400759 AN: 1461842 Hom.: 57731 Cov.: 39 AF XY: 0.272 AC XY: 198100 AN XY: 727230

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.0301

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.287

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.299 AC: 45360 AN: 151944 Hom.: 7350 Cov.: 31 AF XY: 0.295 AC XY: 21932 AN XY: 74248

Gnomad4 AFR AF: 0.383

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.0305

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.264

Alfa AF: 0.284 Hom.: 4846

Bravo AF: 0.291

TwinsUK AF: 0.287 AC: 1063

ALSPAC AF: 0.289 AC: 1114

ESP6500AA AF: 0.376 AC: 1655

ESP6500EA AF: 0.289 AC: 2488

ExAC AF: 0.257 AC: 31144

Asia WGS AF: 0.120 AC: 417 AN: 3478

EpiCase AF: 0.291

EpiControl AF: 0.293

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -

Deficiency of alpha-mannosidase Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, 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 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.010
Dann	Benign	0.46
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.00077	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.72	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.75	N;N
REVEL	Benign	0.10
Sift	Benign	0.58	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;.
Vest4		0.019
MPC		0.56
ClinPred		0.0051	T
GERP RS		-7.4
Varity_R		0.036
gMVP		0.49

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: rs1054486; hg19: chr19-12774208; COSMIC: COSV55471017; COSMIC: COSV55471017;