rs1553250952
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):āc.828C>Gā(p.Tyr276Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y276Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_206933.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.828C>G | p.Tyr276Ter | stop_gained | 5/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.828C>G | p.Tyr276Ter | stop_gained | 5/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.828C>G | p.Tyr276Ter | stop_gained | 5/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.828C>G | p.Tyr276Ter | stop_gained | 5/21 | 1 | |||
USH2A | ENST00000674083.1 | c.828C>G | p.Tyr276Ter | stop_gained | 5/73 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460960Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726790
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 24, 2022 | _x000D_ Criteria applied: PVS1, PM3, PM2_SUP - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 26, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551646). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 23591405). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr276*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2018 | The Y276X variant in the USH2A gene has been reported previously in an individual with retinitis pigmentosa who harbored an additional variant in the USH2A gene in trans (Glockle et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y276X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Y276X as a pathogenic variant. - |
Usher syndrome type 2A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 02, 2022 | _x000D_ Criteria applied: PVS1, PS4_MOD, PM3, PM2_SUP - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 03, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at