rs59357922

Variant names:

• chr19-12655780-G-C
• rs59357922
• NM_000528.4:c.1744C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000528.4(MAN2B1):​c.1744C>G​(p.Gln582Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,610,168 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (14 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.542
• Publications: 1 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, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038622022).
• BP6: Variant 19-12655780-G-C is Benign according to our data. Variant chr19-12655780-G-C is described in ClinVar as Benign. ClinVar VariationId is 457139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00722 (1099/152236) while in subpopulation AFR AF = 0.0255 (1060/41548). AF 95% confidence interval is 0.0242. There are 15 homozygotes in GnomAd4. There are 499 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	NM_000528.4	MANE Select	c.1744C>G	p.Gln582Glu	missense	Exon 14 of 24	NP_000519.2
	MAN2B1	NM_001440570.1		c.1747C>G	p.Gln583Glu	missense	Exon 14 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.1741C>G	p.Gln581Glu	missense	Exon 14 of 24	NP_001166969.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.1744C>G	p.Gln582Glu	missense	Exon 14 of 24	ENSP00000395473.2
	MAN2B1	ENST00000221363.9	TSL:1	c.1741C>G	p.Gln581Glu	missense	Exon 14 of 24	ENSP00000221363.4
	MAN2B1	ENST00000433513.5	TSL:4	n.350C>G		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152118 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00180 AC: 450 AN: 250378 AF XY: 0.00129

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000750 AC: 1094 AN: 1457932 Hom.: 14 Cov.: 31 AF XY: 0.000635 AC XY: 460 AN XY: 724414

African (AFR) AF: 0.0278 AC: 928 AN: 33428

American (AMR) AF: 0.000964 AC: 43 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108888

Other (OTH) AF: 0.00173 AC: 104 AN: 60224

GnomAD4 genome AF: 0.00722 AC: 1099 AN: 152236 Hom.: 15 Cov.: 31 AF XY: 0.00670 AC XY: 499 AN XY: 74444

African (AFR) AF: 0.0255 AC: 1060 AN: 41548

American (AMR) AF: 0.00170 AC: 26 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000871 Hom.: 2

Bravo AF: 0.00821

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of alpha-mannosidase (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.94
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.54
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.078
Sift	Benign	0.14	T
Sift4G	Benign	0.42	T
Polyphen		0.046	B
Vest4		0.082
MVP		0.66
MPC		0.26
ClinPred		0.00064	T
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.44
Mutation Taster		=98/2	polymorphism

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: rs59357922; hg19: chr19-12766594;