rs786204420
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004937.3(CTNS):c.926dup(p.Ser310GlnfsTer55) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T307T) has been classified as Likely benign.
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.926dup | p.Ser310GlnfsTer55 | frameshift_variant | 11/12 | ENST00000046640.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTNS | ENST00000046640.9 | c.926dup | p.Ser310GlnfsTer55 | frameshift_variant | 11/12 | 1 | NM_004937.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461604Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727078
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
Nephropathic cystinosis Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 07, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
Cystinosis Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 29, 2018 | Variant summary: CTNS c.926dupG (p.Ser310GlnfsX55) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.9e-06 in 336774 control chromosomes (gnomAD and publications). c.926dupG has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Cystinosis (Besouw_2012, Kalatzis_2002, Kiehntopf_2002, Shotelersuk_1998). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 27, 2022 | - - |
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Ser310Glnfs*55) in the CTNS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the CTNS protein. This variant is present in population databases (rs786204420, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with cystinosis (PMID: 9792862, 12204010, 12442267, 27734949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1261insG, S310Q. ClinVar contains an entry for this variant (Variation ID: 188714). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at