chr5-149960981-T-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000112.4(SLC26A2):c.-26+2T>C variant causes a splice donor, intron 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
Consequence
NM_000112.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC26A2 | ENST00000286298.5 | c.-26+2T>C | splice_donor_variant, intron_variant | Intron 1 of 2 | 1 | NM_000112.4 | ENSP00000286298.4 | |||
| SLC26A2 | ENST00000433184.1 | c.-306+2T>C | splice_donor_variant, intron_variant | Intron 1 of 2 | 4 | ENSP00000405496.1 | ||||
| SLC26A2 | ENST00000690410.1 | n.207+2T>C | splice_donor_variant, intron_variant | Intron 1 of 1 |
Frequencies
GnomAD3 genomes 0.000542 AC: 82AN: 151424Hom.: 0 Cov.: 33
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
GnomAD4 genome 0.000541 AC: 82AN: 151542Hom.: 0 Cov.: 33 AF XY: 0.000648 AC XY: 48AN XY: 74034
ClinVar
Submissions by phenotype
not provided Pathogenic:5
- -
- -
SLC26A2: PM3:Very Strong, PM1, PM2, PP4 -
The SLC26A2 c.-26+2T>C variant (rs386833492) is reported as a founder variant in the Finnish population, largely in patients affected with diastrophic dysplasia (Hastbacka 1999). This variant is also reported in the homozygous or compound heterozygous state in patients with atelosteogenesis II, diastrophic dysplasia (DTD), diastrophic dysplasia variant, multiple epiphyseal dysplasia (rMED) as well as in the intermediate phenotype between DTD and rMED (Zechi-Ceide 2013). This variant disrupts the canonical splice donor site of intron 1, and functional assays show that patients homozygous for the c.-26+2T>C variant had approximately 5% of correctly spliced mRNA (Hasbacka 1999). This variant is found in the general population with an overall allele frequency of 0.14% (43/31128 alleles), with an increased frequency in the Finnish population of 0.69% in the Genome Aggregation Database (v2.1.1). Based on available information, this variant is considered to be pathogenic. References: Hastbacka J et al. Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Eur J Hum Genet. 1999 Sep;7(6):664-70. PMID: 10482955. Zechi-Ceide RM et al. A compound heterozygote SLC26A2 mutation resulting in robin sequence, mild limbs shortness, accelerated carpal ossification, and multiple epiphysial dysplasia in two Brazilian sisters. A new intermediate phenotype between diastrophic dysplasia and recessive multiple epiphyseal dysplasia. Am J Med Genet A. 2013 Aug;161A(8):2088-94. PMID: 23840040. -
The mRNA expression assay revealed that homozygous patients have a low but detectable level of correctly spliced mRNA, estimated to be approximately 5% of the wild-type allele (PMID: 10482955); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18708426, 34064542, 33726816, 23840040, 21155763, 30423444, 24598000, 21922596, 21077202, 26147798, 27096365, 28569743, 33728303, 32655299, 34831381, 34627339, 37829280, 37265969, 36660027, 36285626, 35611473, 36651276, 36140680, 34493867, 38459613, 10482955, 20301524) -
Diastrophic dysplasia Pathogenic:4Other:1
- -
- -
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. -
- -
- -
Achondrogenesis, type IB Pathogenic:3
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. -
- -
- -
Atelosteogenesis type II Pathogenic:2
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
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. -
- -
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:2
- -
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
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
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at