NM_000441.2:c.1707+6T>C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000441.2(SLC26A4):c.1707+6T>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000441.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1254518Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0AN XY: 635176
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rare genetic deafness Pathogenic:1
The c.1707+6T>C variant in SLC26A4 was absent from large population studies, but has been identified by our laboratory in one individual with hearing loss and e nlarged vestibular aqueducts (EVA) who also carried a pathogenic variant on the other copy of SLC26A4. This variant is located in the 5' splice region. Computat ional tools do not suggest an impact to splicing, though this information is not predictive enough to rule out pathogenicity. However, the presence of this vari ant in combination with a reported pathogenic variant and in an individual with hearing loss and EVA, increases the likelihood that the c.1707+6T>C variant is p athogenic. In summary, although additional studies are required to fully establi sh its clinical significance, the c.1707+6T>C variant is likely pathogenic. -
not provided Uncertain:1
This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 15 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. It affects a nucleotide within the consensus splice site. This variant has been observed in individual(s) with deafness (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 179934). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at