rs763006761
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.1667A>G(p.Tyr556Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,442,458 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y556H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1667A>G | p.Tyr556Cys | missense_variant | 15/21 | ENST00000644269.2 | NP_000432.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1667A>G | p.Tyr556Cys | missense_variant | 15/21 | NM_000441.2 | ENSP00000494017.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250870Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135586
GnomAD4 exome AF: 0.0000104 AC: 15AN: 1442458Hom.: 0 Cov.: 26 AF XY: 0.0000153 AC XY: 11AN XY: 719078
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3Other:1
Affects, no assertion criteria provided | clinical testing;in vitro | National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Aug 20, 2019 | in vitro experiment - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center | Jul 01, 2017 | - - |
Pendred syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 26, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 556 of the SLC26A4 protein (p.Tyr556Cys). This variant is present in population databases (rs763006761, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness and/or Pendred syndrome (PMID: 9618167, 27573290, 28281779). ClinVar contains an entry for this variant (Variation ID: 446456). 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 SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316, 31599023). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at