chr5-149980369-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000112.4(SLC26A2):c.776G>T(p.Gly259Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,896 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G259S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000112.4 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 | UniProt |
---|---|---|---|---|---|---|---|
SLC26A2 | NM_000112.4 | c.776G>T | p.Gly259Val | missense_variant | 3/3 | ENST00000286298.5 | |
SLC26A2 | XM_017009191.3 | c.776G>T | p.Gly259Val | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A2 | ENST00000286298.5 | c.776G>T | p.Gly259Val | missense_variant | 3/3 | 1 | NM_000112.4 | P1 | |
SLC26A2 | ENST00000503336.1 | c.372+2018G>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152054Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251360Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461842Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 727226
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74248
ClinVar
Submissions by phenotype
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the SLC26A2 protein (p.Gly259Val). This variant is present in population databases (rs769319202, gnomAD 0.0009%). This missense change has been observed in individual(s) with diastrophic dysplasia (PMID: 11727031, 15720248). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.803G>T. ClinVar contains an entry for this variant (Variation ID: 555871). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11241838, 11727031) - |
Multiple epiphyseal dysplasia type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 08, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at