rs779791079
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):βc.11875_11876delβ(p.Gln3959AsnfsTer53) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000805 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.0000075 ( 0 hom. )
Consequence
USH2A
NM_206933.4 frameshift
NM_206933.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.91
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-215728219-TTG-T is Pathogenic according to our data. Variant chr1-215728219-TTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215728219-TTG-T is described in Lovd as [Pathogenic]. Variant chr1-215728219-TTG-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.11875_11876del | p.Gln3959AsnfsTer53 | frameshift_variant | 61/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.11875_11876del | p.Gln3959AsnfsTer53 | frameshift_variant | 61/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.11875_11876del | p.Gln3959AsnfsTer53 | frameshift_variant | 61/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251236Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135778
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461880Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727240
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 08, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Gln3959Asnfs*53) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs779791079, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of retinal dystrophy (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 198318). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2018 | The c.11875_11876delCA variant in the USH2A gene has been reported previously in association with Usher syndrome (Dreyer et al., 2008). The c.11875_11876delCA variant causes a frameshift starting with codon Glutamine 3959, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Gln3959AsnfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11875_11876delCA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.11875_11876delCA as a pathogenic variant. - |
Retinitis pigmentosa 39 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.11875_11876del 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, PP3. Based on this evidence we have classified this variant as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 26, 2017 | - - |
Usher syndrome type 2A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 22, 2018 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at