rs386833492
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000112.4(SLC26A2):c.-26+2T>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 151,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SLC26A2
NM_000112.4 splice_donor
NM_000112.4 splice_donor
Scores
1
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 2.99
Genes affected
SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]
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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 0.09954955 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 5-149960981-T-C is Pathogenic according to our data. Variant chr5-149960981-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149960981-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC26A2 | NM_000112.4 | c.-26+2T>C | splice_donor_variant | ENST00000286298.5 | NP_000103.2 | |||
| SLC26A2 | XM_017009191.3 | c.-26+2T>C | splice_donor_variant | XP_016864680.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC26A2 | ENST00000286298.5 | c.-26+2T>C | splice_donor_variant | 1 | NM_000112.4 | ENSP00000286298 | P1 | |||
| SLC26A2 | ENST00000433184.1 | c.-306+2T>C | splice_donor_variant | 4 | ENSP00000405496 | |||||
| SLC26A2 | ENST00000690410.1 | n.207+2T>C | splice_donor_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes 0.000542 AC: 82AN: 151424Hom.: 0 Cov.: 33
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 302Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 234
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GnomAD4 genome 0.000541 AC: 82AN: 151542Hom.: 0 Cov.: 33 AF XY: 0.000648 AC XY: 48AN XY: 74034
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Diastrophic dysplasia Pathogenic:4Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2008 | - - |
| Pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 07, 2021 | - - |
Achondrogenesis, type IB Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | SLC26A2: PM3:Very Strong, PM1, PM2, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 31, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
Atelosteogenesis type II Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 07, 2021 | - - |
| Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NG_007147.2(NM_000112.3):c.-26+2T>C in the SLC26A2 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. Makitie O. et al. reported that one patient was homozygous for the Finnish major SLC26A2 mutation IVS1+2T>C, four were compound heterozygotes with this mutation and Arg279Trp and all of them were affected with multiple epiphyseal dysplasia (PMID: 24598000). The SLC26A2 c.-26+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. - |
Multiple epiphyseal dysplasia type 4 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 07, 2021 | - - |
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 05, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change falls in intron 1 of the SLC26A2 gene. It does not directly change the encoded amino acid sequence of the SLC26A2 protein. This variant is present in population databases (rs386833492, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with SLC26A2-related diseases in affected families (PMID: 10482955, 21077202, 23840040). It is commonly reported in individuals of Finnish ancestry (PMID: 10482955, 21077202, 23840040). ClinVar contains an entry for this variant (Variation ID: 4097). 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. - |
SLC26A2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 10, 2018 | The SLC26A2 c.-26+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product.This variant, which has been described as a founder variant in the Finnish population, has been reported in at least six studies and is found in a total of at least 101 probands including 70 in a homozygous state, 17 in a compound heterozygous state, and 14 in a heterozygous state (Hästbacka et al. 1999; Bonafé et al. 2008; Dwyer et al. 2010; Jackson et al. 2012; Zechi-Ceide et al. 2013; Mäkitie et al. 2015). Of the 101 probands, 77 probands were affected by diastrophic dysplasia, six probands with recessively inherited multiple epiphyseal dysplasia, three probands with a phenotype that was intermediate between diastrophic dysplasia and multiple epiphyseal dysplasia, and one proband with atelosteogenesis. No probands were reported with achondrogenesis or sulfate transporter-related osteochondrodysplasia. The c.-26+2T>C variant is present in at least four unaffected parents in a heterozygous state (Bonafé et al. 2008; Dwyer et al. 2010). The variant was absent from 200 control samples and is reported at a frequency of 0.01515 in the Finnish population of the 1000 Genomes Project. RT-PCR assays using skin fibroblasts from probands homozygous for the c.-26+2T>C variant showed a 5% level of wild type mRNA which was correctly spliced (Hästbacka et al. 1999). Based on the collective evidence, the c.-26+2T>C variant is classified as pathogenic for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Sulfate transporter-related osteochondrodysplasia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2018 | Variant summary: SLC26A2 c.-26+2T>C is located in a canonical splice-site in the 5'UTR 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. This is supported by at least one publication that reports a near complete loss of properly spliced mRNA from patient fibroblasts (Hastbacka_1999). The variant allele was found at a frequency of 0.0014 in 30678 control chromosomes (gnomAD), which does not exceed the maximal expected frequency for a pathogenic variant in the SLC26A2 gene. The c.-26+2T>C variant has been reported in the literature in numerous individuals affected with Sulfate Transporter-Related Osteochondrodysplasia as a homozygous and compound heterozygous allele, and is referred to in the literature as a founder mutation in the Finnish population (Hastbacka_1999). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, though several submitters prior to 2014 classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
3MC syndrome 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at