rs771583281
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.2167+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_206933.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.2167+5G>A | splice_region_variant, intron_variant | 1 | NM_206933.4 | ENSP00000305941.3 | ||||
USH2A | ENST00000366942.3 | c.2167+5G>A | splice_region_variant, intron_variant | 1 | ENSP00000355909.3 | |||||
USH2A | ENST00000674083.1 | c.2167+5G>A | splice_region_variant, intron_variant | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250350Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135302
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727052
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74306
ClinVar
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.2167+5G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change falls in intron 12 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs771583281, gnomAD 0.01%). This variant has been observed in individuals with Usher syndrome 2 or retinitis pigmentosa (PMID: 12112664, 21151602, 24516651, 30190494). This variant is also known as IVS12+5G>A. ClinVar contains an entry for this variant (Variation ID: 552447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20497194). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2024 | This variant is associated with the following publications: (PMID: 20497194, 25525159, 12112664, 25366773, 30190494, 24944099, 24516651, 23647439, 31589614, 33576794, 31456290, 34948090, 34781295, 32188678, 21151602) - |
Usher syndrome type 2A Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 16, 2020 | - - |
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 22, 2019 | - - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2022 | Variant summary: USH2A c.2167+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site and one predicts an extreme weakening of this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in both out-of frame skipping of exon 12 and an in-frame skipping of the exon with the use of an alternate splice site (Jaijo_2011). The variant allele was found at a frequency of 4e-05 in 250350 control chromosomes. This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4e-05 vs 0.011), allowing no conclusion about variant significance. c.2167+5G>A has been reported in the literature in multiple individuals affected with Usher Syndrome or Retinitis Pigmentosa (Avila-Fernandez_2010, Gao_2021, Jaijo_2011, Najera_2002, Columbo_2021), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
USH2A-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 13, 2024 | The USH2A c.2167+5G>A variant is predicted to interfere with splicing. This variant has been reported as pathogenic in patients with Usher syndrome and inherited retinal dystrophies, with functional studies demonstrating it results in exon skipping (Najera et al. 2002. PubMed ID: 12112664; Jaijo et al. 2011. PubMed ID: 20497194; González-Del Pozo et al 2018. PubMed ID: 30190494). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at