rs121434331

chr19-12649418-G-Achr19-12649418-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.2278C>T(p.Arg760Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000621 in 1,610,244 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R760R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.91

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 19-12649418-G-A is Pathogenic according to our data. Variant chr19-12649418-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685.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.2278C>T	p.Arg760Ter	stop_gained	19/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.2275C>T	p.Arg759Ter	stop_gained	19/24
MAN2B1	XM_005259913.3	c.2281C>T	p.Arg761Ter	stop_gained	19/24
MAN2B1	XM_047438841.1	c.1177C>T	p.Arg393Ter	stop_gained	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2278C>T	p.Arg760Ter	stop_gained	19/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.2275C>T	p.Arg759Ter	stop_gained	19/24	1		P4
MAN2B1	ENST00000466794.5	n.2868C>T		non_coding_transcript_exon_variant	17/22	2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151274 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000730

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248886 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134638

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458970 Hom.: 0 Cov.: 32 AF XY: 0.00000827 AC XY: 6 AN XY: 725800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151274 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73842

Gnomad4 AFR AF: 0.0000730

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2017	Variant summary: The MAN2B1 c.2278C>T (p.Arg760X) variant results in a premature termination codon, predicted to cause a truncated or absent MAN2B1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/108116 (1/54058), which does not exceed the estimated maximal expected allele frequency for a pathogenic MAN2B1 variant of 1/632. A publication, Godota_1998, cites the variant in a sibling pair, where both sisters were homozygous for the variant. Authors indicate that the variant causes a Lysosomal alpha-mannosidosis type 2, with a milder phenotype, hypothesized by "The nonsense mutation in the alpha-mannosidase gene is located in exon 19, at a point ~75% along the length of the protein. This nonsense mutation likely encodes an unstable mRNA, such that a relatively stable but defective protein is produced that can show partial activity toward alpha-mannose residues in vivo." In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg760*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of mannosidosis (PMID: 9758606). ClinVar contains an entry for this variant (Variation ID: 1685). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A
Vest4		0.34
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs121434331; hg19: chr19-12760232; COSMIC: COSV55472261; COSMIC: COSV55472261;