19-12655693-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000528.4(MAN2B1):​c.1830+1G>C variant causes a splice donor change. The variant allele was found at a frequency of 0.000167 in 1,608,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 splice_donor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 5.67
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06093544 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-12655693-C-G is Pathogenic according to our data. Variant chr19-12655693-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 21207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12655693-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAN2B1NM_000528.4 linkuse as main transcriptc.1830+1G>C splice_donor_variant ENST00000456935.7 NP_000519.2
MAN2B1NM_001173498.2 linkuse as main transcriptc.1827+1G>C splice_donor_variant NP_001166969.1
MAN2B1XM_005259913.3 linkuse as main transcriptc.1833+1G>C splice_donor_variant XP_005259970.1
MAN2B1XM_047438841.1 linkuse as main transcriptc.729+1G>C splice_donor_variant XP_047294797.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAN2B1ENST00000456935.7 linkuse as main transcriptc.1830+1G>C splice_donor_variant 1 NM_000528.4 ENSP00000395473 A1O00754-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152118
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000925
AC:
23
AN:
248630
Hom.:
0
AF XY:
0.000104
AC XY:
14
AN XY:
134398
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000326
Gnomad NFE exome
AF:
0.000142
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000176
AC:
257
AN:
1456706
Hom.:
0
Cov.:
31
AF XY:
0.000152
AC XY:
110
AN XY:
723972
show subpopulations
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:
0.000413
Gnomad4 NFE exome
AF:
0.000204
Gnomad4 OTH exome
AF:
0.000150
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152118
Hom.:
0
Cov.:
31
AF XY:
0.0000942
AC XY:
7
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:12Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2012- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 25, 2019Variant summary: MAN2B1 c.1830+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 248630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (9.3e-05 vs 0.0016). c.1830+1G>C has been reported in the literature as one of the most common disease causing variants in multiple individuals affected with Alpha-Mannosidosis (example, Riise Stensland_2012, Berg_1999). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained within the context of this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 01, 2021NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant classified as pathogenic in the context of alpha-mannosidosis. c.1830+1G>C has been observed in cases with relevant disease (PMID: 9915946, 22161967). Functional assessments of this variant are not available in the literature. c.1830+1G>C has been observed in population frequency databases (gnomAD: FIN 0.03%). In summary, NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 26, 2020Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available, intron 14). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (24 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0704 - Comparable variant has low previous evidence for pathogenicity (Borgwardt, L. et al. (2015); Riise Stensland, H. et al. (2012)). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; Matlach, J. et al (2018)). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterFeb 02, 2022PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change affects a donor splice site in intron 14 of the MAN2B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is present in population databases (rs80338677, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with mannosidosis (PMID: 9915946, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS14+1G>C. ClinVar contains an entry for this variant (Variation ID: 21207). 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 submitterclinical testingBaylor GeneticsMar 15, 2024- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 22, 2020- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterApr 09, 2021- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 17, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 20, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 20, 2024Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9915946, 22161967, 31980526, 34429528, 38382588, 38107468) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
28
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
GERP RS
3.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.95
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338677; hg19: chr19-12766507; COSMIC: COSV55476199; COSMIC: COSV55476199; API