rs1133330

Variant names:

• chr19-12661276-C-T
• rs1133330
• NM_000528.4:c.1010G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-12661276-C-T
• chr19-12661276-C-A
• chr19-12661276-C-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000528.4(MAN2B1):​c.1010G>A​(p.Arg337Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,609,782 control chromosomes in the GnomAD database, including 108,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9273 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98881 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0290
• Publications: 50 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 -16 ACMG points.

• BP6: Variant 19-12661276-C-T is Benign according to our data. Variant chr19-12661276-C-T is described in ClinVar as Benign. ClinVar VariationId is 93207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

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.1010G>A	p.Arg337Gln	missense	Exon 7 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.1010G>A	p.Arg337Gln	missense	Exon 7 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.1010G>A	p.Arg337Gln	missense	Exon 7 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.1010G>A	p.Arg337Gln	missense	Exon 7 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.1010G>A	p.Arg337Gln	missense	Exon 7 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.1010G>A	p.Arg337Gln	missense	Exon 7 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51559 AN: 151944 Hom.: 9270 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.0549

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.307 AC: 77077 AN: 251434 AF XY: 0.312

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.358 AC: 522125 AN: 1457720 Hom.: 98881 Cov.: 32 AF XY: 0.357 AC XY: 258625 AN XY: 725386

African (AFR) AF: 0.322 AC: 10748 AN: 33394

American (AMR) AF: 0.199 AC: 8877 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12814 AN: 26082

East Asian (EAS) AF: 0.0497 AC: 1973 AN: 39686

South Asian (SAS) AF: 0.231 AC: 19920 AN: 86198

European-Finnish (FIN) AF: 0.291 AC: 15511 AN: 53380

Middle Eastern (MID) AF: 0.432 AC: 2477 AN: 5734

European-Non Finnish (NFE) AF: 0.387 AC: 429024 AN: 1108308

Other (OTH) AF: 0.345 AC: 20781 AN: 60236

GnomAD4 genome AF: 0.339 AC: 51573 AN: 152062 Hom.: 9273 Cov.: 32 AF XY: 0.331 AC XY: 24624 AN XY: 74312

African (AFR) AF: 0.324 AC: 13441 AN: 41466

American (AMR) AF: 0.261 AC: 3980 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1694 AN: 3470

East Asian (EAS) AF: 0.0549 AC: 284 AN: 5176

South Asian (SAS) AF: 0.223 AC: 1077 AN: 4830

European-Finnish (FIN) AF: 0.291 AC: 3077 AN: 10556

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26869 AN: 67968

Other (OTH) AF: 0.357 AC: 754 AN: 2112

Alfa AF: 0.373 Hom.: 55127

Bravo AF: 0.335

TwinsUK AF: 0.384 AC: 1424

ALSPAC AF: 0.389 AC: 1499

ESP6500AA AF: 0.313 AC: 1379

ESP6500EA AF: 0.399 AC: 3431

ExAC AF: 0.310 AC: 37687

Asia WGS AF: 0.158 AC: 551 AN: 3478

EpiCase AF: 0.407

EpiControl AF: 0.396

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Deficiency of alpha-mannosidase (5)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.00050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N
PhyloP100		-0.029
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.22
Sift	Benign	0.33	T
Sift4G	Benign	0.23	T
Polyphen		0.046	B
Vest4		0.032
MPC		0.65
ClinPred		0.0077	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -4

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

Other links and lift over

dbSNP: rs1133330; hg19: chr19-12772090; COSMIC: COSV55471603; COSMIC: COSV55471603;