rs993185407
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_206933.4(USH2A):c.2168-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_206933.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.2168-2A>G | splice_acceptor_variant, intron_variant | ENST00000307340.8 | NP_996816.3 | |||
USH2A | NM_007123.6 | c.2168-2A>G | splice_acceptor_variant, intron_variant | NP_009054.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.2168-2A>G | splice_acceptor_variant, intron_variant | 1 | NM_206933.4 | ENSP00000305941.3 | ||||
USH2A | ENST00000366942.3 | c.2168-2A>G | splice_acceptor_variant, intron_variant | 1 | ENSP00000355909.3 | |||||
USH2A | ENST00000674083.1 | c.2168-2A>G | splice_acceptor_variant, intron_variant | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461538Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727074
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 06, 2018 | - - |
Retinitis pigmentosa 39 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Usher syndrome type 2A Pathogenic:2
Pathogenic, no assertion criteria provided | research | National Institute on Deafness and Communication Disorders, National Institutes of Health | Dec 10, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change affects an acceptor splice site in intron 12 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Usher syndrome (Invitae). 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: 556562). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 29, 2017 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 12, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at