rs45576136

Positions:

• chr19-12663382-G-A
• chr19-12663382-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000528.4(MAN2B1):​c.844C>T​(p.Pro282Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,946 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.45

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020751774).
• BP6: Variant 19-12663382-G-A is Benign according to our data. Variant chr19-12663382-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558862.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr19-12663382-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00281 (427/152130) while in subpopulation AMR AF= 0.00426 (65/15272). AF 95% confidence interval is 0.00382. There are 1 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.844C>T	p.Pro282Ser	missense_variant	6/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.844C>T	p.Pro282Ser	missense_variant	6/24
MAN2B1	XM_005259913.3	c.844C>T	p.Pro282Ser	missense_variant	6/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.844C>T	p.Pro282Ser	missense_variant	6/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.844C>T	p.Pro282Ser	missense_variant	6/24	1		P4
MAN2B1	ENST00000462144.1	n.37C>T		non_coding_transcript_exon_variant	1/2	3
MAN2B1	ENST00000466794.5	n.826C>T		non_coding_transcript_exon_variant	6/22	2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152012 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00260 AC: 653 AN: 251474 Hom.: 1 AF XY: 0.00265 AC XY: 360 AN XY: 135920

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00374 AC: 5460 AN: 1461816 Hom.: 15 Cov.: 31 AF XY: 0.00360 AC XY: 2619 AN XY: 727202

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00361

Gnomad4 NFE exome AF: 0.00430

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00281 AC: 427 AN: 152130 Hom.: 1 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74356

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00337 Hom.: 3

Bravo AF: 0.00281

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00249 AC: 302

EpiCase AF: 0.00420

EpiControl AF: 0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAN2B1: BS2 -

Deficiency of alpha-mannosidase Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 26, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

MAN2B1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.70	D;.
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.021	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.38
Sift	Benign	0.046	D;T
Sift4G	Benign	0.18	T;T
Polyphen		0.87	P;.
Vest4		0.39
MVP		0.84
MPC		1.3
ClinPred		0.075	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.76

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: rs45576136; hg19: chr19-12774196;