1-216246784-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.2610C>A(p.Cys870*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,614,016 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 Pathogenic (★★). 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.2610C>A | p.Cys870* | stop_gained | Exon 13 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000366942.3 | c.2610C>A | p.Cys870* | stop_gained | Exon 13 of 21 | 1 | ENSP00000355909.3 | |||
USH2A | ENST00000674083.1 | c.2610C>A | p.Cys870* | stop_gained | Exon 13 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250752Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135480
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727224
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:4
This sequence change creates a premature translational stop signal (p.Cys870*) 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 (rs767078782, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 22135276, 28559085). 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: 557167). For these reasons, this variant has been classified as Pathogenic. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29196752, 28944237, 22135276, 28981474, 28559085, 25558175, 25333064, 27460420, 26766544, 33576794) -
USH2A: PM3:Very Strong, PVS1, PM2 -
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Usher syndrome type 2A Pathogenic:4
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Retinal dystrophy Pathogenic:3
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Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:2
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Retinitis pigmentosa 39 Pathogenic:2
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Usher syndrome;C5680250:Rare genetic deafness Pathogenic:1
The p.Cys870X variant in USH2A has been previously reported in >10 probands with Usher syndrome, who were either homozygous or compound heterozygous for another USH2A variant (Baux 2017, Bonnet 2016, Comander 2017, Krawitz 2014, Le Quesne S tabej 2012, Neuhaus 2017, Sodi 2014, Weisschuh 2016). This variant has been iden tified in 0.003% (4/126016) of European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org); however, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense varia nt leads to a premature termination codon at position 870, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on t he previously reported probands with Usher syndrome, the predicted impact of the variant, and its low frequency in the general population. ACMG/AMP criteria app lied: PVS1, PM3_VeryStrong, PM2, PP4. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at