rs61234887

Variant names:

• chr19-12649959-C-T
• rs61234887
• NM_000528.4:c.2221G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000528.4(MAN2B1):​c.2221G>A​(p.Gly741Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,613,858 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (78 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (62 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.40
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004482478).
• BP6: Variant 19-12649959-C-T is Benign according to our data. Variant chr19-12649959-C-T is described in ClinVar as Benign. ClinVar VariationId is 235571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0555 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.2221G>A	p.Gly741Arg	missense	Exon 18 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.2224G>A	p.Gly742Arg	missense	Exon 18 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2218G>A	p.Gly740Arg	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.2221G>A	p.Gly741Arg	missense	Exon 18 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.2218G>A	p.Gly740Arg	missense	Exon 18 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.2269G>A	p.Gly757Arg	missense	Exon 18 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2546 AN: 151868 Hom.: 78 Cov.: 30

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00866

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0140

GnomAD2 exomes AF: 0.00433 AC: 1088 AN: 251496 AF XY: 0.00318

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00178 AC: 2598 AN: 1461872 Hom.: 62 Cov.: 34 AF XY: 0.00151 AC XY: 1099 AN XY: 727232

African (AFR) AF: 0.0594 AC: 1989 AN: 33478

American (AMR) AF: 0.00371 AC: 166 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5758

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1112004

Other (OTH) AF: 0.00439 AC: 265 AN: 60396

GnomAD4 genome AF: 0.0168 AC: 2556 AN: 151986 Hom.: 78 Cov.: 30 AF XY: 0.0160 AC XY: 1189 AN XY: 74296

African (AFR) AF: 0.0574 AC: 2377 AN: 41390

American (AMR) AF: 0.00865 AC: 132 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67978

Other (OTH) AF: 0.0138 AC: 29 AN: 2096

Alfa AF: 0.00666 Hom.: 43

Bravo AF: 0.0193

ESP6500AA AF: 0.0574 AC: 253

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00516 AC: 627

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of alpha-mannosidase (3)
-	-	3	not provided (3)
-	-	1	Intellectual disability (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0045	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.4
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.63		Loss of ubiquitination at K740 (P = 0.0255)
MVP		0.92
MPC		0.90
ClinPred		0.035	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.67
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61234887; hg19: chr19-12760773; COSMIC: COSV106370686; COSMIC: COSV106370686;