rs1554095397
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000286298.5(SLC26A2):c.1987G>A(p.Gly663Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,094 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G663G) has been classified as Likely benign.
Frequency
Consequence
ENST00000286298.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A2 | NM_000112.4 | c.1987G>A | p.Gly663Arg | missense_variant | 3/3 | ENST00000286298.5 | NP_000103.2 | |
SLC26A2 | XM_017009191.3 | c.1987G>A | p.Gly663Arg | missense_variant | 3/4 | XP_016864680.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A2 | ENST00000286298.5 | c.1987G>A | p.Gly663Arg | missense_variant | 3/3 | 1 | NM_000112.4 | ENSP00000286298 | P1 | |
SLC26A2 | ENST00000503336.1 | c.372+3229G>A | intron_variant | 3 | ENSP00000426053 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461840Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 727214
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74438
ClinVar
Submissions by phenotype
Achondrogenesis, type IB Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 24, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 12, 2020 | - - |
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 27, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 663 of the SLC26A2 protein (p.Gly663Arg). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 16642506). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A2 protein function. ClinVar contains an entry for this variant (Variation ID: 550616). This missense change has been observed in individual(s) with SLC26A2-related conditions (PMID: 16642506, 31880411). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. - |
Osteochondrodysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 19, 2024 | Variant summary: SLC26A2 c.1987G>A (p.Gly663Arg) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251228 control chromosomes (gnomAD). However, the variant was reported in the Japanese population with an allele frequency of 0.0019 (jMorp database). This frequency is lower than the maximum expected allele frequency for a pathogenic variant in SLC26A2 causing Sulfate Transporter-Related Osteochondrodysplasias (0.003). The variant, c.1987G>A, has been reported in the literature in compound heterozygous- and homozygous state in multiple Japanese individuals (i.e. affected fetuses) with Sulfate Transporter-Related Osteochondrodysplasia (Maeda_2006, Sato_2019). These data indicate that the variant is very likely to be associated with disease. One of these publication reported that the variant protein was exclusively observed only in the cytoplasm in an eukaryotic expression system, whereas the wild-type protein was observed on the plasma membrane (with no cytoplasmic or nuclear staining), suggesting that it most likely represents a functionally null mutation, because it is improperly localized to the cytoplasm (Maeda_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16642506, 31880411). ClinVar contains an entry for this variant (Variation ID: 550616). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Multiple epiphyseal dysplasia type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2017 | - - |
SLC26A2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2017 | The SLC26A2 c.1987G>A (p.Gly663Arg) missense variant was reported in one fetus in a compound heterozygous state with a second missense variant. The patient was diagnosed with an intermediate phenotype between diastrophic dysplasia and atelosteogenesis, type II. The unaffected mother of the patient was a carrier of the p.Gly663Arg variant, which was absent in 48 healthy controls (Maeda et al. 2006). No patients were reported with achondrogenesis, multiple epiphyseal dysplasia or sulfate transporter-related osteochondrodysplasia. The p.Gly663Arg variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database, in a region with good sequence coverage and hence is presumed to be rare. Functionally, Maeda et al. (2006) showed that in HEK293 cells, the p.Gly663Arg variant protein was located within the cytoplasm as compared to wild type protein which was present along the plasma membrane of the cell, with no cytoplasmic or nuclear staining. Based on the evidence, the p.Gly663Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at