rs759623796
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004937.3(CTNS):c.771_793del(p.Gly258SerfsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I253I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004937.3 frameshift
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 |
---|---|---|---|---|---|---|---|
CTNS | NM_004937.3 | c.771_793del | p.Gly258SerfsTer30 | frameshift_variant | 10/12 | ENST00000046640.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTNS | ENST00000046640.9 | c.771_793del | p.Gly258SerfsTer30 | frameshift_variant | 10/12 | 1 | NM_004937.3 | P1 | |
CTNS-AS1 | ENST00000575741.1 | non_coding_transcript_exon_variant | 1/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152072Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251296Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135878
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460070Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 726384
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74420
ClinVar
Submissions by phenotype
Nephropathic cystinosis Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 26, 2021 | This 23 bp deletion in CTNS has been previously reported in individuals with nephropathic cystinosis. This CTNS variant (rs759623796) is rare (<0.1%) in a large population dataset (gnomAD: 7/251296 total alleles; 0.003%; no homozygotes) and there is an entry in ClinVar. This frameshift variant results in a premature stop codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 16, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Cystinosis Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 05, 2017 | Variant summary: The variant results in the deletion of a 23 nucleotides leading to a termination codon at position 288 of CTNS. The variant was present at a low frequency in the large and broad cohorts of the ExAC project (3/121,076 chromosomes) while it was observed in multiple CTNS patients in the literature. Considering all evidence, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 02, 2021 | - - |
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 05, 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: 496276). This variant is also known as c.1109_1131del23. This premature translational stop signal has been observed in individuals with cystinosis (PMID: 10556299, 26266097). This variant is present in population databases (rs759623796, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Gly258Serfs*30) in the CTNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNS are known to be pathogenic (PMID: 9537412, 27102039). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at