chr17-3656724-AACG-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_004937.3(CTNS):βc.614_616delβ(p.Asp205del) variant causes a 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 (β β ). Synonymous variant affecting the same amino acid position (i.e. N204N) has been classified as Likely benign.
Frequency
Consequence
NM_004937.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTNS | NM_004937.3 | c.614_616del | p.Asp205del | inframe_deletion | 9/12 | ENST00000046640.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTNS | ENST00000046640.9 | c.614_616del | p.Asp205del | inframe_deletion | 9/12 | 1 | NM_004937.3 | P1 | |
CTNS-AS1 | ENST00000575741.1 | n.532+129_532+131del | intron_variant, non_coding_transcript_variant | 5 |
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
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 12, 2014 | - - |
Cystinosis Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2022 | 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 11, 2023 | This variant is present in population databases (rs760256854, gnomAD 0.01%). 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 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. For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this variant affects CTNS function (PMID: 15128704). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 188718). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at