chr17-3655305-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004937.3(CTNS):​c.414G>A​(p.Trp138Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

CTNS
NM_004937.3 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 7.39
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-3655305-G-A is Pathogenic according to our data. Variant chr17-3655305-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3655305-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CTNSNM_004937.3 linkuse as main transcriptc.414G>A p.Trp138Ter stop_gained 7/12 ENST00000046640.9 NP_004928.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CTNSENST00000046640.9 linkuse as main transcriptc.414G>A p.Trp138Ter stop_gained 7/121 NM_004937.3 ENSP00000046640 P1O60931-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251492
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000664
AC:
97
AN:
1461888
Hom.:
0
Cov.:
49
AF XY:
0.0000688
AC XY:
50
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000863
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000943
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephropathic cystinosis Pathogenic:4Other:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 27, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 1999- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 20, 2019NM_004937.2(CTNS):c.414G>A(W138*) is classified as pathogenic in the context of cystinosis. Sources cited for classification include the following: PMID 9792862, 10482956 and 11855931. Classification of NM_004937.2(CTNS):c.414G>A(W138*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJun 27, 2016The known nonsense variant, c.414G>A (p.Trp138Ter) introduces a stop codon at position 138 leading to a truncated cystinosin protein. In affected individuals within the American population, this variant is relatively common (~10%) (Shotelersuk V et al., 1998; Town et al. 1998; McGowan-Jordan J et al.1999), indicating that the prevalence of this variant in affected individuals is significantly higher than in controls. Several loss-of-function pathogenic variants (nonsense, frameshift, splice-site) have been reported, including a nonsense variant further downstream in exon 11 (Kalatzis V and Antignac C, 2003), suggesting loss-of-function as a mechanism of disease. The variant is observed in population databases (ExAc, 1000 Genomes, ESP) a frequency below what is expected carrier rate based on disease prevalence. This substitution co-segregates with disease (Town et al. 1998, McGowan-Jordan J et al.1999). This variant has recently been classified as pathogenic by a reputable clinical laboratory (Emory). Therefore, this variant is best interpreted as a Pathogenic variant for nephropathic cystinosis. We have confirmed this finding in our laboratory using Sanger sequencing -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 24, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 13, 2022Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9537412, 25525159, 9792862, 20301574) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024CTNS: PVS1, PM3:Strong, PM2 -
Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 11, 2022- -
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 10, 2023This sequence change creates a premature translational stop signal (p.Trp138*) 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 present in population databases (rs113994205, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with cystinosis (PMID: 9537412, 9792862, 10482956). ClinVar contains an entry for this variant (Variation ID: 4443). 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, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
49
DANN
Uncertain
1.0
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.87
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.39
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.39
Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113994205; hg19: chr17-3558599; API