19-12663723-G-C

Variant names:

• chr19-12663723-G-C
• rs117843968
• NM_000528.4:c.743C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

MAN2B1 Gene-Disease associations (from GenCC):

• alpha-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000528.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	NM_000528.4	MANE Select	c.743C>G	p.Pro248Arg	missense	Exon 5 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.743C>G	p.Pro248Arg	missense	Exon 5 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.743C>G	p.Pro248Arg	missense	Exon 5 of 24	NP_001166969.1	O00754-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.743C>G	p.Pro248Arg	missense	Exon 5 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.743C>G	p.Pro248Arg	missense	Exon 5 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.743C>G	p.Pro248Arg	missense	Exon 5 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of alpha-mannosidase (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.53		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
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs117843968; hg19: chr19-12774537;