rs876657730
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_206933.4(USH2A):c.486-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000274 in 1,460,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_206933.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.486-1G>C | splice_acceptor_variant | ENST00000307340.8 | |||
USH2A | NM_007123.6 | c.486-1G>C | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.486-1G>C | splice_acceptor_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000366942.3 | c.486-1G>C | splice_acceptor_variant | 1 | |||||
USH2A | ENST00000674083.1 | c.486-1G>C | splice_acceptor_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250644Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135436
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460708Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726670
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome type 2A Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 27, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2017 | The c.486-1 G>C splice site variant in the USH2A gene has been previously reported in association with Usher syndrome (Cremers et al., 2007; Neuhaus et al., 2017). This variant destroys the canonical splice acceptor site in intron 2, and is expected to cause abnormal gene splicing. The c.486-1 G>C variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider c.486-1G>C to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 25, 2022 | ClinVar contains an entry for this variant (Variation ID: 228413). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with USH2A-related conditions (PMID: 24154662, 32037395). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). - |
Retinitis pigmentosa 39 Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 28, 2023 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 19, 2015 | The c.486-1G>C variant in USH2A has been reported in at least one individual wit h hearing loss (Cremers 2007), and was absent from large population studies. Thi s variant occurs in the invariant region (- 1,2) of the splice consensus sequenc e and is predicted to cause altered splicing leading to an abnormal or absent pr otein. Loss of function of the USH2A gene is an established disease mechanism in Usher syndrome. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant. - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at