rs367543075

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_152490.5(B3GALNT2):​c.824_825dupTT​(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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 0.678
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 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 rank MANE Protein UniProt
B3GALNT2NM_152490.5 linkc.824_825dupTT p.Ile276LeufsTer26 frameshift_variant Exon 7 of 12 ENST00000366600.8 NP_689703.1 Q8NCR0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
B3GALNT2ENST00000366600.8 linkc.824_825dupTT p.Ile276LeufsTer26 frameshift_variant Exon 7 of 12 1 NM_152490.5 ENSP00000355559.3 Q8NCR0-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152146
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:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
251380
Hom.:
0
AF XY:
0.000236
AC XY:
32
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000431
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000292
AC:
427
AN:
1461806
Hom.:
0
Cov.:
31
AF XY:
0.000257
AC XY:
187
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000363
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152146
Hom.:
0
Cov.:
31
AF XY:
0.0000942
AC XY:
7
AN XY:
74322
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:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000291
Hom.:
0
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other: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
May 31, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 05, 2019
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 12, 2017
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 25, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 30, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 28, 2024
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

second B3GALNT2 in trans (Missense-Variant, VUS) -

not provided Pathogenic:2Other:1
Dec 21, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

-
Leiden Muscular Dystrophy pages (B3GALNT2)
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

B3GALNT2-related disorder Pathogenic:1
Jun 24, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The B3GALNT2 c.824_825dupTT variant is predicted to result in a frameshift and premature protein termination (p.Ile276Leufs*26). This variant has been reported in the compound heterozygous state to be causative for dystroglycanopathy in two unrelated families (Stevens et al. 2013. PubMed ID: 23453667; Maroofian et al. 2017. PubMed ID: 29273094). This variant is reported in 0.043% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in B3GALNT2 are expected to be pathogenic, and this variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/132981). Given all the evidence, we too interpret c.824_825dup (p.Ile276Leufs*26) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs367543075; hg19: chr1-235628968; API