rs567709615
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP3_Strong
The ENST00000328863.8(CLRN1):c.434-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000824 in 1,534,600 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
ENST00000328863.8 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLRN1 | NM_174878.3 | c.433+1061A>T | intron_variant | ENST00000327047.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLRN1 | ENST00000327047.6 | c.433+1061A>T | intron_variant | 1 | NM_174878.3 | P1 | |||
ENST00000469268.1 | n.235+49651T>A | intron_variant, non_coding_transcript_variant | 4 | ||||||
CLRN1-AS1 | ENST00000476886.5 | n.123+87915T>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.000657 AC: 100AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000507 AC: 68AN: 134166Hom.: 0 AF XY: 0.000411 AC XY: 30AN XY: 73078
GnomAD4 exome AF: 0.000843 AC: 1165AN: 1382366Hom.: 1 Cov.: 30 AF XY: 0.000831 AC XY: 567AN XY: 682132
GnomAD4 genome AF: 0.000657 AC: 100AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42AN XY: 74372
ClinVar
Submissions by phenotype
Usher syndrome type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 15, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 07, 2018 | The c.434-2A>T variant in CLRN1 has been previously identified by our laboratory in five individuals with hearing loss, but none of these individuals had a vari ant affecting the remaining copy of the CLRN1 gene. This variant has been identi fied in 0.12% (81/68182) of European chromosomes by the Genome Aggregation Datab ase (http://gnomad.broadinstitute.org/). This variant is located at the -2 splic e site position near exon 3 of an alternate transcript (NM_001195794.1) of the C LRN1 gene, and is predicted to impact splicing of this transcript. However, in a ll other transcripts of the gene, including the major transcript (NM_174878.2), the variant lies in an intronic region that is distant from the splice sites of exons expressed in those transcripts and is not predicted to impact their splici ng. While this alternate transcript (NM_001195794.1) is reportedly expressed in the retina (Vastinsalo 2011), to date, pathogenic variants have not been reporte d in exon 3 of this transcript in individuals with Usher syndrome. Therefore, it is not clear whether abnormal splicing affecting only the alternate transcript can cause disease. In summary, the clinical significance of this variant is unce rtain. ACMG/AMP Criteria applied: PP3, BS1_Supporting. - |
Hearing impairment Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PVS1_Strong, PM2_Supporting, BP4_Supporting - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2016 | The c.434-2A>T variant in the CLRN1 gene has been reported previously in an individual with Usher syndrome, however a second variant was not identified (Bonnet et al., 2016). This splice site variant destroys the canonical splice acceptor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.434-2A>T variant was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. We interpret c.434-2A>T as a variant of uncertain significance. - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 16, 2019 | This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: PM2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at