NM_000528.4:c.747C>T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 197683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12663719-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.747C>T	p.Thr249Thr	synonymous_variant	Exon 5 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.747C>T	p.Thr249Thr	synonymous_variant	Exon 5 of 24		NP_001166969.1
MAN2B1	XM_005259913.3	c.747C>T	p.Thr249Thr	synonymous_variant	Exon 5 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.747C>T	p.Thr249Thr	synonymous_variant	Exon 5 of 24	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.8	c.747C>T	p.Thr249Thr	synonymous_variant	Exon 5 of 24	1		ENSP00000221363.4
MAN2B1	ENST00000486847.2	c.450C>T	p.Thr150Thr	synonymous_variant	Exon 3 of 4	4		ENSP00000470174.1
MAN2B1	ENST00000466794.5	n.729C>T		non_coding_transcript_exon_variant	Exon 5 of 22	2

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

GnomAD3 exomes AF: 0.0133 AC: 3267 AN: 246476 Hom.: 274 AF XY: 0.00949 AC XY: 1270 AN XY: 133808

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 SAS exome AF: 0.0000328

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

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.00924

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000294

Gnomad4 OTH exome AF: 0.0100

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

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0214 Hom.: 157

Bravo AF: 0.0581

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 21, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Deficiency of alpha-mannosidase Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Mar 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.42
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs61737536; hg19: chr19-12774533; COSMIC: COSV55471031; COSMIC: COSV55471031;