rs367543075
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152490.5(B3GALNT2):c.825_826insTT(p.Ile276LeufsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
B3GALNT2
NM_152490.5 frameshift
NM_152490.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.678
Genes affected
B3GALNT2 (HGNC:28596): (beta-1,3-N-acetylgalactosaminyltransferase 2) This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel carbohydrate structure, on N- and O-glycans. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-235465651-T-TAA is Pathogenic according to our data. Variant chr1-235465651-T-TAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
B3GALNT2 | NM_152490.5 | c.825_826insTT | p.Ile276LeufsTer26 | frameshift_variant | 7/12 | ENST00000366600.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
B3GALNT2 | ENST00000366600.8 | c.825_826insTT | p.Ile276LeufsTer26 | frameshift_variant | 7/12 | 1 | NM_152490.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152146Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000211 AC: 53AN: 251380Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135862
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GnomAD4 exome AF: 0.000292 AC: 427AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.000257 AC XY: 187AN XY: 727206
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 28, 2024 | second B3GALNT2 in trans (Missense-Variant, VUS) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Ile276Leufs*26) in the B3GALNT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in B3GALNT2 are known to be pathogenic (PMID: 23453667). This variant is present in population databases (rs367543075, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy and/or congenital muscular dystrophy-dystroglycanopathy (PMID: 23453667, 29273094). It has also been observed to segregate with disease in related individuals. This variant is also known as c.822_823dup. ClinVar contains an entry for this variant (Variation ID: 132981). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2023 | Variant summary: B3GALNT2 c.824_825dupTT (p.Ile276LeufsX26) 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 allele was found at a frequency of 0.00021 in 251380 control chromosomes (gnomAD). c.824_825dupTT has been reported in the literature in the compound heterozygous state in individuals affected with and/or with features of Muscular Dystrophy-Dystroglycanopathy (congenital With Brain And Eye Anomalies) and in two siblings presenting with mild intellectual disability and behavioral problems but without muscular involvement (e.g. Stevens_2013, Maroofian_2017, Marangoni_2022). These data indicate that the variant is likely to be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function found the variant failed to restore IIH6 staining in a complementation assay, resulting in <10% of WT activity (Maroofian_2017). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Oct 12, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 05, 2019 | - - |
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy pages (B3GALNT2) | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29273094, 35456500, 31980526, 34906519, 23453667) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at