chr19-12655693-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, intron 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
Consequence
NM_000528.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.1830+1G>C | splice_donor_variant, intron_variant | Intron 14 of 23 | ENST00000456935.7 | NP_000519.2 | ||
MAN2B1 | NM_001173498.2 | c.1827+1G>C | splice_donor_variant, intron_variant | Intron 14 of 23 | NP_001166969.1 | |||
MAN2B1 | XM_005259913.3 | c.1833+1G>C | splice_donor_variant, intron_variant | Intron 14 of 23 | XP_005259970.1 | |||
MAN2B1 | XM_047438841.1 | c.729+1G>C | splice_donor_variant, intron_variant | Intron 7 of 16 | XP_047294797.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152118Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000925 AC: 23AN: 248630Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134398
GnomAD4 exome AF: 0.000176 AC: 257AN: 1456706Hom.: 0 Cov.: 31 AF XY: 0.000152 AC XY: 110AN XY: 723972
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74284
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:12Other:1
- -
PVS1, PM2, PM3 -
- -
This 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. -
- -
- -
- -
NM_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. -
- -
- -
Based 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 -
Variant 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. -
- -
Inborn genetic diseases Pathogenic:1
- -
not provided Pathogenic:1
Canonical 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at