19-12663723-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000528.4(MAN2B1):c.743C>G(p.Pro248Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P248L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.743C>G	p.Pro248Arg	missense_variant	5/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.743C>G	p.Pro248Arg	missense_variant	5/24
MAN2B1	XM_005259913.3	c.743C>G	p.Pro248Arg	missense_variant	5/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.743C>G	p.Pro248Arg	missense_variant	5/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.743C>G	p.Pro248Arg	missense_variant	5/24	1		P4
MAN2B1	ENST00000486847.2	c.446C>G	p.Pro149Arg	missense_variant	3/4	4
MAN2B1	ENST00000466794.5	n.725C>G		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the MAN2B1 protein (p.Pro248Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.020	D;D;.
Sift4G	Uncertain	0.041	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.69
MutPred		0.53		Loss of catalytic residue at P247 (P = 0.016);Loss of catalytic residue at P247 (P = 0.016);.;
MVP		0.91
MPC		1.5
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12774537;