rs781223647
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.187C>T(p.Arg63Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,596 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R63R) 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.187C>T | p.Arg63Ter | stop_gained | 2/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.187C>T | p.Arg63Ter | stop_gained | 2/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.187C>T | p.Arg63Ter | stop_gained | 2/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.187C>T | p.Arg63Ter | stop_gained | 2/21 | 1 | |||
USH2A | ENST00000674083.1 | c.187C>T | p.Arg63Ter | stop_gained | 2/73 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250920Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135582
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461578Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727070
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74234
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change creates a premature translational stop signal (p.Arg63*) 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 (rs781223647, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 10909849, 23924366, 28559085). ClinVar contains an entry for this variant (Variation ID: 556744). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2022 | 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12786748, 23924366, 25366773, 10909849, 27318125, 25558175, 24853665, 22135276, 21738395, 12525556, 20591486, 27957503, 28559085, 34948090, 35457016, 36140798, 31144483, 34828430, 34416374, 30948794, 31266775, 33576794, 32675063, 34781295) - |
Retinitis pigmentosa 39 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Usher syndrome type 2A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 09, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 15, 2018 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 19, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at