chr7-107683356-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP3PP5
The NM_000441.2(SLC26A4):c.918+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.918+2T>C | splice_donor_variant | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.918+2T>C | splice_donor_variant | NM_000441.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251256Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461036Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726878
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2023 | Variant summary: SLC26A4 c.918+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two computational tools predict a significant impact on normal splicing, suggesting the variant abolishes a canonical 5' splicing donor site, while one predicts the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251256 control chromosomes. c.918+2T>C has been reported in the literature in individuals affected with hearing loss (Chai_2013, Goncalves_2016, Rentorff_2013, Cengiz_2017), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 27, 2021 | NM_000441.1(SLC26A4):c.918+2T>C is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.918+2T>C has been observed in cases with relevant disease (PMID: 23918157, 23336812, 27214836). Functional assessments of this variant are not available in the literature. c.918+2T>C has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_000441.1(SLC26A4):c.918+2T>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change affects a donor splice site in intron 7 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 23918157, 27214836). ClinVar contains an entry for this variant (Variation ID: 370108). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29739340, 31589614, 27214836, 23918157, 28964290, 26990548, 36147510, 24007330, 23336812, 31541171) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at