chr19-12649932-G-A

Variant names:

• chr19-12649932-G-A
• rs80338680
• NM_000528.4:c.2248C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM5 PP3_Moderate PP5_Very_Strong

The NM_000528.4(MAN2B1):​c.2248C>T​(p.Arg750Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,602,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000697259: a functional study showed that the variant protein was misfolded and arrested in the ER as inactive single-chain form, and patients and transfected cell lines both had almost no detectable enzyme activity (Gotoda_1998, Hansen_2004).; SCV000914830: Nearly absent enzyme activity due to misfolded protein arrested in the endoplasmic reticulum as inactive single-chain forms has been demonstrated in COS1 and COS7 cells transfected with the p.Arg750Trp variant (Gotoda et al. 1998; Hansen et al. 2004).; SCV000953586: Experimental studies have shown that this missense change affects MAN2B1 function (PMID:9758606, 15035660).; SCV001653107: In vitro functional studies support that this variant impacts protein function (Hansen 2004 PMID:15035660, Khan 2009 PMID:19958498).; SCV001247979: PS3:Supporting". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R750Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1 O:1
• Conservation: PhyloP100: 2.08
• Publications: 29 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000697259: a functional study showed that the variant protein was misfolded and arrested in the ER as inactive single-chain form, and patients and transfected cell lines both had almost no detectable enzyme activity (Gotoda_1998, Hansen_2004).; SCV000914830: Nearly absent enzyme activity due to misfolded protein arrested in the endoplasmic reticulum as inactive single-chain forms has been demonstrated in COS1 and COS7 cells transfected with the p.Arg750Trp variant (Gotoda et al. 1998; Hansen et al. 2004).; SCV000953586: Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 9758606, 15035660).; SCV001653107: In vitro functional studies support that this variant impacts protein function (Hansen 2004 PMID: 15035660, Khan 2009 PMID: 19958498).; SCV001247979: PS3:Supporting
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12649931-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587572.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 19-12649932-G-A is Pathogenic according to our data. Variant chr19-12649932-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2248C>T	p.Arg750Trp	missense	Exon 18 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.2251C>T	p.Arg751Trp	missense	Exon 18 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2245C>T	p.Arg749Trp	missense	Exon 18 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.2248C>T	p.Arg750Trp	missense	Exon 18 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.2245C>T	p.Arg749Trp	missense	Exon 18 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.2296C>T	p.Arg766Trp	missense	Exon 18 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 45 AN: 144416 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000704

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000422

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251482 AF XY: 0.000258

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000158 AC: 230 AN: 1457926 Hom.: 0 Cov.: 34 AF XY: 0.000160 AC XY: 116 AN XY: 725240

African (AFR) AF: 0.0000599 AC: 2 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.000677 AC: 36 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.000169 AC: 187 AN: 1109204

Other (OTH) AF: 0.0000666 AC: 4 AN: 60092

GnomAD4 genome AF: 0.000311 AC: 45 AN: 144502 Hom.: 0 Cov.: 30 AF XY: 0.000343 AC XY: 24 AN XY: 70014

African (AFR) AF: 0.000104 AC: 4 AN: 38332

American (AMR) AF: 0.0000703 AC: 1 AN: 14222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4634

European-Finnish (FIN) AF: 0.00118 AC: 11 AN: 9336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000422 AC: 28 AN: 66346

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	1	-	Deficiency of alpha-mannosidase (17)
5	-	-	not provided (5)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.92
MPC		0.89
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.80
gMVP		0.88
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs80338680; hg19: chr19-12760746; COSMIC: COSV55470688; COSMIC: COSV55470688;