rs1021413948
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_153700.2(STRC):c.2303_2313+1delGGAAGCTGCAGG(p.Lys769fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00087 ( 0 hom., cov: 2)
Exomes 𝑓: 0.0013 ( 9 hom. )
Failed GnomAD Quality Control
Consequence
STRC
NM_153700.2 frameshift, splice_donor, splice_region, intron
NM_153700.2 frameshift, splice_donor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0640
Genes affected
STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| STRC | ENST00000450892.7 | c.2303_2313+1delGGAAGCTGCAGG | p.Lys769fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | 6/29 | 5 | NM_153700.2 | ENSP00000401513.2 | ||
| ENSG00000284772 | ENST00000643290.1 | n.*1524_*1535delGGAAGCTGCAGG | downstream_gene_variant | ENSP00000495476.1 |
Frequencies
GnomAD3 genomes 0.000870 AC: 6AN: 6900Hom.: 0 Cov.: 2
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GnomAD3 exomes AF: 0.000248 AC: 10AN: 40334Hom.: 0 AF XY: 0.000291 AC XY: 6AN XY: 20618
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00133 AC: 351AN: 263976Hom.: 9 AF XY: 0.00132 AC XY: 184AN XY: 139404
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GnomAD4 genome 0.000870 AC: 6AN: 6894Hom.: 0 Cov.: 2 AF XY: 0.000966 AC XY: 3AN XY: 3106
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2022 | The c.2303_2313+1del variant in STRC has been identified by our laboratory in one family with hearing loss who had a likely pathogenic variant on the remaining copy of STRC and segregated in 2 affected family members. This variant has also been previously identified in 5 individuals with hearing loss, one of whom was homozygous, another who was compound heterozygous for an additional missense variant in STRC, and three of whom were heterozygous and lacked a second STRC variant (Francey 2012 PMID: 22147502, Vona 2015 PMID: 26011646, Brozkova 2020 PMID: 32860223). Data from large population studies is insufficient to assess the frequency of this variant. This variant is a deletion of 12 nucleotides including the last 11 nucleotides of exon 6 and the nucleotide at the +1 position in the intron. While this variant deletes the invariant +1 position of the splice consensus sequence, splice prediction tools indicate that the variant may result in an alternate splice site which would delete 12 nucleotides and therefore could result in an in-frame deletion of four amino acid residues. Furthermore, the sequence of the 12 nucleotides that are deleted are part of a repetitive sequence, and species conservation shows that the four deleted amino acids are only present in 1 other mammal (chimpanzee). This raises the possibility that an alternate splice site at this position may not impact the protein. However, it is also possible that this variant would cause altered splicing leading to an abnormal or absent protein, due the fact that this variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.2303_2313+1del variant is uncertain due to the lack of frequency information and the conflicting conservation and computational data. ACMG/AMP Criteria applied: PM3, PP1_Moderate, PP3. - |
Autosomal recessive nonsyndromic hearing loss 16 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at