rs45576136

Variant names:

• chr19-12663382-G-A
• rs45576136
• NM_000528.4:c.844C>T
• MAN2B1 p.Pro282Ser

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/22 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
• Publications: 11 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: Myriad Women's Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 558862.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

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.844C>T	p.Pro282Ser	missense	Exon 6 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.844C>T	p.Pro282Ser	missense	Exon 6 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.844C>T	p.Pro282Ser	missense	Exon 6 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.844C>T	p.Pro282Ser	missense	Exon 6 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.844C>T	p.Pro282Ser	missense	Exon 6 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.844C>T	p.Pro282Ser	missense	Exon 6 of 24	ENSP00000634062.1

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

GnomAD2 exomes AF: 0.00260 AC: 653 AN: 251474 AF XY: 0.00265

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33478

American (AMR) AF: 0.00420 AC: 188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00361 AC: 193 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00430 AC: 4780 AN: 1111954

Other (OTH) AF: 0.00373 AC: 225 AN: 60392

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

African (AFR) AF: 0.000723 AC: 30 AN: 41490

American (AMR) AF: 0.00426 AC: 65 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 67988

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00329 Hom.: 3

Bravo AF: 0.00281

EpiCase AF: 0.00420

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Deficiency of alpha-mannosidase (3)
-	-	1	MAN2B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.4
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.38
Sift	Benign	0.046	D
Sift4G	Benign	0.18	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.76
Mutation Taster		=87/13	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45576136;

hg19: chr19-12774196;

COSMIC: COSV107282932;

COSMIC: COSV107282932;