rs1406466561

chr19-12647594-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000528.4(MAN2B1):c.2669C>G(p.Ser890Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S890S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.04

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12647594-G-C is Pathogenic according to our data. Variant chr19-12647594-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 552770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.2669C>G	p.Ser890Ter	stop_gained	22/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.2666C>G	p.Ser889Ter	stop_gained	22/24
MAN2B1	XM_005259913.3	c.2672C>G	p.Ser891Ter	stop_gained	22/24
MAN2B1	XM_047438841.1	c.1568C>G	p.Ser523Ter	stop_gained	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2669C>G	p.Ser890Ter	stop_gained	22/24	1	NM_000528.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460368 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2019	Variant summary: MAN2B1 c.2669C>G (p.Ser890X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245278 control chromosomes (gnomAD). c.2669C>G has been reported in the literature in compound heterozygote individuals affected with Alpha-Mannosidosis (Rise Stensland_2012). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552770). This premature translational stop signal has been observed in individuals with mannosidosis (PMID: 22161967). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser890*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.28
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1406466561; hg19: chr19-12758408;