rs1054487

chr19-12661351-G-Achr19-12661351-G-Cchr19-12661351-G-T

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.935C>T(p.Thr312Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,610,788 control chromosomes in the GnomAD database, including 121,803 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T312N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13848 hom., cov: 32)
  • Exomes 𝑓: 0.37 (107955 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.96

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=1.6364455E-4).
• BP6: Variant 19-12661351-G-A is Benign according to our data. Variant chr19-12661351-G-A is described in ClinVar as [Benign]. Clinvar id is 93218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12661351-G-A is described in Lovd as [Benign]. Variant chr19-12661351-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.935C>T	p.Thr312Ile	missense_variant	7/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.935C>T	p.Thr312Ile	missense_variant	7/24
MAN2B1	XM_005259913.3	c.935C>T	p.Thr312Ile	missense_variant	7/24
MAN2B1	XM_047438841.1	c.-84C>T		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.935C>T	p.Thr312Ile	missense_variant	7/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.935C>T	p.Thr312Ile	missense_variant	7/24	1		P4
MAN2B1	ENST00000462144.1	n.128C>T		non_coding_transcript_exon_variant	2/2	3
MAN2B1	ENST00000466794.5	n.917C>T		non_coding_transcript_exon_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62314 AN: 151958 Hom.: 13826 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.418

GnomAD3 exomes AF: 0.332 AC: 83511 AN: 251472 Hom.: 16124 AF XY: 0.333 AC XY: 45309 AN XY: 135912

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.0505

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.373 AC: 544784 AN: 1458712 Hom.: 107955 Cov.: 33 AF XY: 0.371 AC XY: 269149 AN XY: 725794

Gnomad4 AFR exome AF: 0.557

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.0497

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.410 AC: 62360 AN: 152076 Hom.: 13848 Cov.: 32 AF XY: 0.400 AC XY: 29725 AN XY: 74340

Gnomad4 AFR AF: 0.549

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.519

Gnomad4 EAS AF: 0.0544

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.415

Alfa AF: 0.395 Hom.: 26087

Bravo AF: 0.418

TwinsUK AF: 0.392 AC: 1454

ALSPAC AF: 0.396 AC: 1527

ESP6500AA AF: 0.537 AC: 2366

ESP6500EA AF: 0.411 AC: 3533

ExAC AF: 0.340 AC: 41261

EpiCase AF: 0.418

EpiControl AF: 0.409

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	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 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2017	Variant summary: The MAN2B1 c.935C>T (p.Thr312Ile) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 94194/277144 control (gnomAD) chromosomes (18497 homozygotes) at a frequency of 0.3398739, which is approximately 215 times the estimated maximal expected allele frequency of a pathogenic MAN2B1 variant (0.0015811), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -

Deficiency of alpha-mannosidase Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

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	0.086
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.35
Dann	Benign	0.13
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.00016	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.8	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.6	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	B;.
Vest4		0.072
MPC		0.61
ClinPred		0.0065	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.35

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: rs1054487; hg19: chr19-12772165; COSMIC: COSV55471011; COSMIC: COSV55471011;