rs786204423
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_004937.3(CTNS):c.614_616delACG(p.Asp205del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004937.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CTNS | NM_004937.3 | c.614_616delACG | p.Asp205del | disruptive_inframe_deletion | Exon 9 of 12 | ENST00000046640.9 | NP_004928.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151740Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251348Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461498Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727064
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151740Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74088
ClinVar
Submissions by phenotype
Nephropathic cystinosis Pathogenic:2
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Cystinosis Pathogenic:1Other:1
Variant summary: CTNS c.614_616delACG (p.Asp205del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 251348 control chromosomes. c.614_616delACG has been reported in the literature in individuals affected with Cystinosis in homozygous and compound heterozygous states. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
This variant, c.614_616del, results in the deletion of 1 amino acid(s) of the CTNS protein (p.Asp205del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760256854, gnomAD 0.01%). This variant has been observed in individual(s) with cystinosis (PMID: 9792862, 10556299). 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: 188718). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CTNS function (PMID: 15128704). This variant disrupts a region of the CTNS protein in which other variant(s) (p.Asp205Asn) have been determined to be pathogenic (PMID: 9792862, 22528245, 28983406). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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