chr7-107698042-T-TC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.1547dupC(p.Ser517PhefsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000437 in 1,602,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000441.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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SLC26A4 | ENST00000644269.2 | c.1547dupC | p.Ser517PhefsTer10 | frameshift_variant | Exon 14 of 21 | NM_000441.2 | ENSP00000494017.1 | |||
SLC26A4 | ENST00000477350.5 | n.394dupC | non_coding_transcript_exon_variant | Exon 4 of 5 | 4 | |||||
SLC26A4 | ENST00000480841.5 | n.396dupC | non_coding_transcript_exon_variant | Exon 5 of 8 | 3 | |||||
SLC26A4 | ENST00000644846.1 | n.257dupC | non_coding_transcript_exon_variant | Exon 4 of 10 | ENSP00000494344.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251180Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135766
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1449788Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1AN XY: 722220
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74484
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:4
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with enlarged vestibular aqueduct (PMID: 27997596, PMID: 24612839, ClinVar). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Ser517Phefs*10) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs776972633, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with non-syndromic hearing loss (PMID: 19786220, 20842945, 21704276). ClinVar contains an entry for this variant (Variation ID: 188759). For these reasons, this variant has been classified as Pathogenic. -
Identified in additional patients with sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 27247933, 30733538, 35939872, 36597107); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34416374, 21961810, 20842945, 19786220, 12676893, 24341454, 23918157, 23151031, 23151025, 21704276, 30733538, 30275481, 34170635, 32447495, 35314707, 36126472, 36597107, 27247933, 33199029, 35982127, 27997596, 35939872) -
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
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Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at