chr7-107694617-G-GCAGT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.1342-2_1343dupAGTC(p.Leu450fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000134 in 1,608,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000441.2 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251046Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135656
GnomAD4 exome AF: 0.000139 AC: 203AN: 1456246Hom.: 0 Cov.: 30 AF XY: 0.000139 AC XY: 101AN XY: 724902
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change falls in intron 11 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. This variant is present in population databases (rs756270039, gnomAD 0.009%). This variant has been observed in individuals with deafness with enlargement of the vestibular aqueduct (PMID: 15689455, 19204907). This variant is also known as c.1342-2_1343dup (p.Leu450Glyfs*19) if splicing occurs at the native splice site. It is also referred to as c.1340_1343dup and 1343–1344insAGTC in the literature. ClinVar contains an entry for this variant (Variation ID: 43506). For these reasons, this variant has been classified as Pathogenic. -
Frameshift variant predicted to result in protein truncation or nonsense-mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease; In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 19204907, 21704276, 31589614, 15689455) -
Pendred syndrome Pathogenic:1
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Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
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Rare genetic deafness Pathogenic:1
The 1342-2_1343dupAGTC variant in SLC26A4 has been reported as a compound hetero zygous variant in 3 individuals with enlarged vestibular aqueducts (EVA) and has been identified by our laboratory in 3 other individuals each of whom has a sec ond pathogenic SLC26A4 variant (Choi 2009, LMM unpublished data). This variant l eads to the duplication of a conserved splice site at the beginning of exon 12, which could either deleteriously affect splicing of the transcript or cause a fr ameshift if 4 additional bases are included in the exon. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM). -
SLC26A4-related disorder Pathogenic:1
The SLC26A4 c.1342-2_1343dupAGTC variant is predicted to result in a duplication affecting a canonical splice site. This variant has been reported along with a second SLC26A4 variant in individuals with an enlarged vestibular aqueduct (described as 1343-1344insAGTC in Pryor et al. 2005. PubMed ID: 15689455; described as c.1340_1343dup in Choi et al. 2009. PubMed ID: 19204907). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107335062-G-GCAGT). Taken together, this variant is interpreted as pathogenic. -
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