1-216325499-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_206933.4(USH2A):c.949C>A(p.Arg317Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_206933.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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USH2A | ENST00000307340.8 | c.949C>A | p.Arg317Arg | synonymous_variant | Exon 6 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000366942.3 | c.949C>A | p.Arg317Arg | synonymous_variant | Exon 6 of 21 | 1 | ENSP00000355909.3 | |||
USH2A | ENST00000674083.1 | c.949C>A | p.Arg317Arg | synonymous_variant | Exon 6 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250788Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135506
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461598Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727106
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74300
ClinVar
Submissions by phenotype
not provided Pathogenic:7
USH2A: PM3:Very Strong, PVS1, PM2 -
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Non-canonical splice site variant demonstrated to result in loss-of-function (Vache et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27957503, 15043528, 15015129, 30904819, 20513143, 26927203, 24944099, 23891399, 28944237, 15241801, 15325563, 21569298, 18273898, 16963483, 25575603, 30609409) -
This sequence change affects codon 317 of the USH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs111033272, gnomAD 0.006%). This variant has been observed in individual(s) with Usher syndrome type IIa or nonsydromic retinitis pigmentosa (PMID: 15241801, 20513143, 21569298, 26927203). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2358). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20513143). For these reasons, this variant has been classified as Pathogenic. -
Usher syndrome type 2A Pathogenic:7
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This variant was classified as: Pathogenic. -
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This variant was in trans with USH2A c.1172G>T in a patient presenting with clinical signs that correspond with Usher syndrome. This variant is not present in a homozygous state in population database gnomAD (v4.1.0). It was reported as pathogenic multiple times in ClinVar. It was featured in multiple articles concerning Usher syndrome type 2 (PMID 20513143, 27460420, 15241801, 26927203). Based on the evidence outlined above, the variant was classified as pathogenic. -
Retinitis pigmentosa 39 Pathogenic:3
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Retinal dystrophy Pathogenic:2
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Usher syndrome type 2 Pathogenic:1
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Blindness;C1840457:Retinal pigment epithelial atrophy;C4520679:Abnormal macular morphology;C4551714:Rod-cone dystrophy;C4551715:Pigmentary retinopathy Pathogenic:1
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Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
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Rare genetic deafness Pathogenic:1
The p.Arg317Arg (NM_206933.2 c.949C>A) variant in USH2A has been reported in 9 i ndividuals with Usher syndrome (Pennings 2004, Seyedahmadi 2004, Cremers 2007, D reyer 2008, Vache 2010, Bonnet 2011). A second variant in USH2A was found in tr ans in at least 3 of these individuals (Pennings 2004, Vache 2010, Bonnet 2011). This variant has also been reported in ClinVar (Variation ID#2358) as pathogeni c. mRNA studies show that this variant leads to abnormal splicing and a frameshi ft (Vache 2010). This variant has been identified in (8/126206) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs111033272). Although this variant has been seen in the general pop ulation, its frequency is low enough to be consistent with a recessive carrier f requency. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon functional evide nce and its occurrence in individuals with this disease. ACMG/AMP Criteria appli ed: PVS1, PM2, PM3, PP5. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at