17-3648911-ATCCTT-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004937.3(CTNS):c.206_210del(p.Ile69ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000186 in 1,613,190 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. I69I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CTNS
NM_004937.3 frameshift
NM_004937.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.11
Genes affected
CTNS (HGNC:2518): (cystinosin, lysosomal cystine transporter) This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-3648911-ATCCTT-A is Pathogenic according to our data. Variant chr17-3648911-ATCCTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 455787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3648911-ATCCTT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTNS | NM_004937.3 | c.206_210del | p.Ile69ArgfsTer5 | frameshift_variant | 5/12 | ENST00000046640.9 | |
LOC105371493 | XR_007065579.1 | n.1934+1248_1934+1252del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTNS | ENST00000046640.9 | c.206_210del | p.Ile69ArgfsTer5 | frameshift_variant | 5/12 | 1 | NM_004937.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460968Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726880
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nephropathic cystinosis Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 02, 2022 | - - |
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Ile69Argfs*5) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystinosis (PMID: 10625078). ClinVar contains an entry for this variant (Variation ID: 455787). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2021 | Variant summary: CTNS c.206_210delTCCTT (p.Ile69ArgfsX5) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251456 control chromosomes. c.206_210delTCCTT has been reported as a homozygous mutation in at least one individual affected with Cystinosis (e.g. Shotelersuk_1998). These data indicate that the variant may be associated with disease. Fibroblasts from this patient were assessed as having higher levels of intracellular cystine compared to normal controls (e.g. Vitcitsky_2010). One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at