rs748961218
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_206933.4(USH2A):c.2168-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,586 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 Pathogenic (★★).
Frequency
Consequence
NM_206933.4 splice_acceptor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.2168-1G>C | splice_acceptor_variant | ENST00000307340.8 | |||
USH2A | NM_007123.6 | c.2168-1G>C | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.2168-1G>C | splice_acceptor_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000366942.3 | c.2168-1G>C | splice_acceptor_variant | 1 | |||||
USH2A | ENST00000674083.1 | c.2168-1G>C | splice_acceptor_variant |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248174Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134820
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461520Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727052
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74282
ClinVar
Submissions by phenotype
Usher syndrome type 2A Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Sep 06, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 556842). Disruption of this splice site has been observed in individuals with USH2A-related conditions (PMID: 17405132, 28559085, 29151245, 31054281). This variant is present in population databases (rs748961218, gnomAD 0.0009%). 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2018 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2018 | - - |
Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 15, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at