chr5-149981550-T-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000112.4(SLC26A2):c.1957T>A(p.Cys653Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000112.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251278Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135808
GnomAD4 exome AF: 0.000111 AC: 162AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.000132 AC XY: 96AN XY: 727224
GnomAD4 genome AF: 0.000125 AC: 19AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74318
ClinVar
Submissions by phenotype
not provided Pathogenic:7
SLC26A2: PM3:Very Strong, PM2, PP4, PS3:Supporting -
The SLC26A2 c.1957T>A; p.Cys653Ser variant (rs104893924) is one of the most frequently found pathogenic SLC26A2 variants and has been described in the homozygous and compound heterozygous states in individuals with recessive multiple epiphyseal dysplasia (rMED) and diastrophic dysplasia (DTD; Czarny-Ratajczak 2010, Hinrichs 2010, Makitie 2003, Rossi 2001). It contains an entry in ClinVar (Variation ID: 4098) and is observed in the European (non-Finnish) population at an overall frequency of 0.027% (35/129008 alleles) in the Genome Aggregation Database. The cysteine at codon 653 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In addition, functional in vitro studies of the variant protein demonstrate reduced protein expression and sulfate transport function when compared to wild type protein (Karniski 2004). Based on available information, this variant is considered pathogenic. REFERENCES Czarny-Ratajczak M et al. New intermediate phenotype between MED and DD caused by compound heterozygous mutations in the DTDST gene. Am J Med Genet A. 2010; 152A(12): 3036-3042. Hinrichs T et al. Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene--phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: case report. BMC Musculoskelet Disord. 2010;11:110. Karniski L. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet. 2004; 13(19): 2165-2171. Makitie O et al. Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign. Am J Med Genet A. 2003;122A(3): 187-192. Rossi A et al. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001; 17(3): 159-171. -
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies revealed significantly reduced protein expression in cells with mutant protein, as compared to wild type cells (Karniski et al., 2004); This variant is associated with the following publications: (PMID: 12966518, 30578734, 35026467, 21077204, 20525296, 11241838, 21922596, 11448940, 29724173, 30423444, 29758562, 30462520, 28941661, 30080953, 31980526, 31589614, 33724725, 21155763, 34064542, 33728303, 32633442, 34958143, 34974531, 15294877, 12525546) -
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Achondrogenesis, type IB Pathogenic:3
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NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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. -
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Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:3
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 653 of the SLC26A2 protein (p.Cys653Ser). This variant is present in population databases (rs104893924, gnomAD 0.03%). This missense change has been observed in individuals with diastrophic dysplasia or epiphyseal dysplasia (PMID: 11241838, 12966518, 20525296, 21077204). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4098). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC26A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 15294877). For these reasons, this variant has been classified as Pathogenic. -
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Diastrophic dysplasia Pathogenic:2Other:1
NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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. -
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SLC26A2-related disorder Pathogenic:2
The c.1957T>A;p.(Cys653Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 4098; PMID: 20301524; 11241838; 12966518; 20525296; 21077204; 21922596) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11448940; 15294877) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104893924– gnomAD 0.001249%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Cys653Ser) was detected in trans with a pathogenic variant (PMID: 12966518; 20525296; 21077204; 21922596) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 21077204) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -
The SLC26A2 c.1957T>A variant is predicted to result in the amino acid substitution p.Cys653Ser. This variant has been documented to be causative for SLC26A2-related disorders (Makitie et al. 2003. PubMed ID: 12966518; Hinrichs et al. 2010. PubMed ID: 20525296; Czarny-Ratajczak et al. 2010. PubMed ID: 21077204). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Multiple epiphyseal dysplasia type 4 Pathogenic:2
NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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. -
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Atelosteogenesis type II Pathogenic:1
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Sulfate transporter-related osteochondrodysplasia Pathogenic:1
Variant summary: SLC26A2 c.1957T>A (p.Cys653Ser) results in a non-conservative amino acid change located in the STAS domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 276994 control chromosomes (gnomAD). The variant, c.1957T>A, has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with recessive Multiple epiphyseal dysplasia (Ballhausen_2003, Jackson_2012). These data indicate that the variant is very likely to be associated with disease. A functional study, Karniski_2004, found the variant to have ~55% stimulated sulfate transport. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
3MC syndrome 2 Pathogenic:1
NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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. -
Connective tissue disorder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at