17-3656759-C-CA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004937.3(CTNS):c.646dup(p.Thr216AsnfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000806 in 1,613,368 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. L215L) 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.646dup | p.Thr216AsnfsTer12 | frameshift_variant | 9/12 | ENST00000046640.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTNS | ENST00000046640.9 | c.646dup | p.Thr216AsnfsTer12 | frameshift_variant | 9/12 | 1 | NM_004937.3 | P1 | |
CTNS-AS1 | ENST00000575741.1 | n.532+96_532+97insT | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251168Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135854
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461280Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726960
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
Nephropathic cystinosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2016 | - - |
Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 24, 2022 | This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371084). This variant is also known as c.985insA, p.Thr216Asn. This premature translational stop signal has been observed in individuals with cystinosis (PMID: 9792862, 18178779, 19863563, 27858370). This sequence change creates a premature translational stop signal (p.Thr216Asnfs*12) 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). - |
Cystinosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 02, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at