rs61737536

Variant names:

• chr19-12663719-G-A
• rs61737536
• NM_000528.4:c.747C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000528.4(MAN2B1):​c.747C>T​(p.Thr249Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,612,522 control chromosomes in the GnomAD database, including 1,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (634 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (612 hom.)
• Consequence: MAN2B1 NM_000528.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.20
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-12663719-G-A is Benign according to our data. Variant chr19-12663719-G-A is described in ClinVar as Benign. ClinVar VariationId is 197683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 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.747C>T	p.Thr249Thr	synonymous	Exon 5 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.747C>T	p.Thr249Thr	synonymous	Exon 5 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.747C>T	p.Thr249Thr	synonymous	Exon 5 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.747C>T	p.Thr249Thr	synonymous	Exon 5 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.747C>T	p.Thr249Thr	synonymous	Exon 5 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.747C>T	p.Thr249Thr	synonymous	Exon 5 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7637 AN: 152142 Hom.: 635 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0133 AC: 3267 AN: 246476 AF XY: 0.00949

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.00825

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000532

Gnomad OTH exome AF: 0.00612

GnomAD4 exome AF: 0.00517 AC: 7554 AN: 1460262 Hom.: 612 Cov.: 32 AF XY: 0.00451 AC XY: 3274 AN XY: 726444

African (AFR) AF: 0.184 AC: 6143 AN: 33454

American (AMR) AF: 0.00924 AC: 411 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53022

Middle Eastern (MID) AF: 0.00784 AC: 44 AN: 5610

European-Non Finnish (NFE) AF: 0.000294 AC: 327 AN: 1111476

Other (OTH) AF: 0.0100 AC: 606 AN: 60308

GnomAD4 genome AF: 0.0502 AC: 7637 AN: 152260 Hom.: 634 Cov.: 32 AF XY: 0.0484 AC XY: 3607 AN XY: 74456

African (AFR) AF: 0.175 AC: 7282 AN: 41512

American (AMR) AF: 0.0156 AC: 239 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68024

Other (OTH) AF: 0.0345 AC: 73 AN: 2116

Alfa AF: 0.0214 Hom.: 157

Bravo AF: 0.0581

Asia WGS AF: 0.0100 AC: 36 AN: 3478

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.42
DANN	Benign	0.56
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs61737536; hg19: chr19-12774533; COSMIC: COSV55471031; COSMIC: COSV55471031;