rs34544747

chr19-12657035-C-A

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.1441G>T(p.Ala481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,611,712 control chromosomes in the GnomAD database, including 1,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A481A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.067 (880 hom., cov: 32)
  • Exomes 𝑓: 0.019 (976 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.73

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=0.0021640658).
• BP6: Variant 19-12657035-C-A is Benign according to our data. Variant chr19-12657035-C-A is described in ClinVar as [Benign]. Clinvar id is 93210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12657035-C-A is described in Lovd as [Benign]. Variant chr19-12657035-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.1441G>T	p.Ala481Ser	missense_variant	12/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.1438G>T	p.Ala480Ser	missense_variant	12/24
MAN2B1	XM_005259913.3	c.1444G>T	p.Ala482Ser	missense_variant	12/24
MAN2B1	XM_047438841.1	c.340G>T	p.Ala114Ser	missense_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.1441G>T	p.Ala481Ser	missense_variant	12/24	1	NM_000528.4	A1

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10209 AN: 152148 Hom.: 878 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0650

GnomAD3 exomes AF: 0.0262 AC: 6482 AN: 247852 Hom.: 382 AF XY: 0.0225 AC XY: 3020 AN XY: 134506

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0644

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00424

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0193 AC: 28198 AN: 1459446 Hom.: 976 Cov.: 31 AF XY: 0.0185 AC XY: 13467 AN XY: 726046

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0650

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.00115

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0672 AC: 10229 AN: 152266 Hom.: 880 Cov.: 32 AF XY: 0.0648 AC XY: 4825 AN XY: 74448

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.0391

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00641

Gnomad4 FIN AF: 0.000564

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0643

Alfa AF: 0.0256 Hom.: 322

Bravo AF: 0.0766

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.184 AC: 809

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0286 AC: 3467

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0184

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

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	Jun 07, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.065	T;.
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.0018	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.23
Sift	Benign	0.59	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.37	B;.
Vest4		0.11
MPC		0.52
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.076
gMVP		0.53

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: rs34544747; hg19: chr19-12767849; COSMIC: COSV55471993; COSMIC: COSV55471993;