17-3656487-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_004937.3(CTNS):​c.462T>G​(p.Ser154Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S154S) has been classified as Benign.

Frequency

Genomes: š‘“ 0.0 ( 0 hom., cov: 17)
Exomes š‘“: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CTNS
NM_004937.3 missense, splice_region

Scores

11
4
4
Splicing: ADA: 0.00007464
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32
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]
CTNS-AS1 (HGNC:56090): (CTNS antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain PQ-loop 1 (size 66) in uniprot entity CTNS_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004937.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTNSNM_004937.3 linkc.462T>G p.Ser154Arg missense_variant, splice_region_variant Exon 8 of 12 ENST00000046640.9 NP_004928.2 O60931-1A0A0S2Z3K3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTNSENST00000046640.9 linkc.462T>G p.Ser154Arg missense_variant, splice_region_variant Exon 8 of 12 1 NM_004937.3 ENSP00000046640.4 O60931-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
129606
Hom.:
0
Cov.:
17
FAILED QC
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000818
AC:
2
AN:
244426
Hom.:
0
AF XY:
0.00000755
AC XY:
1
AN XY:
132416
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457946
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
725056
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
129606
Hom.:
0
Cov.:
17
AF XY:
0.00
AC XY:
0
AN XY:
62010
Gnomad4 AFR
AF:
0.00
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:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Mar 03, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.462T>G (p.S154R) alteration is located in exon 8 (coding exon 6) of the CTNS gene. This alteration results from a T to G substitution at nucleotide position 462, causing the serine (S) at amino acid position 154 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.45
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.99
D;.;.;.;.
Eigen
Benign
-0.040
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.93
D;D;.;D;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.3
M;M;.;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-4.7
D;D;.;.;.
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;.;.;.
Sift4G
Uncertain
0.0020
D;D;.;D;D
Polyphen
1.0
D;D;.;.;.
Vest4
0.95
MutPred
0.85
Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);.;.;Gain of MoRF binding (P = 0.0284);
MVP
0.93
MPC
0.72
ClinPred
0.96
D
GERP RS
1.3
Varity_R
0.92
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000075
dbscSNV1_RF
Benign
0.098
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs77453839; hg19: chr17-3559781; API