rs141212446

Variant names:

• chr19-12649920-C-T
• rs141212446
• NM_000528.4:c.2260G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000528.4(MAN2B1):​c.2260G>A​(p.Glu754Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,084 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 0.249
• Publications: 5 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000528.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.024946094).
• BP6: Variant 19-12649920-C-T is Benign according to our data. Variant chr19-12649920-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328262.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (196/151972) while in subpopulation NFE AF = 0.00234 (159/67946). AF 95% confidence interval is 0.00204. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.2260G>A	p.Glu754Lys	missense	Exon 18 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.2263G>A	p.Glu755Lys	missense	Exon 18 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2257G>A	p.Glu753Lys	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.2260G>A	p.Glu754Lys	missense	Exon 18 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.2257G>A	p.Glu753Lys	missense	Exon 18 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.2308G>A	p.Glu770Lys	missense	Exon 18 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 151856 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.00123 AC: 309 AN: 251484 AF XY: 0.00115

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00177 AC: 2592 AN: 1461112 Hom.: 7 Cov.: 34 AF XY: 0.00175 AC XY: 1274 AN XY: 726876

African (AFR) AF: 0.000419 AC: 14 AN: 33452

American (AMR) AF: 0.00105 AC: 47 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26128

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

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86228

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53396

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5528

European-Non Finnish (NFE) AF: 0.00212 AC: 2355 AN: 1111618

Other (OTH) AF: 0.00143 AC: 86 AN: 60338

GnomAD4 genome AF: 0.00129 AC: 196 AN: 151972 Hom.: 0 Cov.: 30 AF XY: 0.00123 AC XY: 91 AN XY: 74272

African (AFR) AF: 0.000314 AC: 13 AN: 41422

American (AMR) AF: 0.000524 AC: 8 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 67946

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.00187 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.00164

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Deficiency of alpha-mannosidase (5)
-	2	1	not provided (3)
-	-	1	MAN2B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.33
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.39	N
PhyloP100		0.25
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.30
MVP		0.53
MPC		0.27
ClinPred		0.0013	T
GERP RS		-1.3
Varity_R		0.055
gMVP		0.57
Mutation Taster		=98/2	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: rs141212446; hg19: chr19-12760734; COSMIC: COSV106370724; COSMIC: COSV106370724;