rs113994208

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_004937.3(CTNS):c.613G>A(p.Asp205Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,244 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D205D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CTNS
NM_004937.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.42

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 links:

CTNS-AS1 (HGNC:56090): (CTNS antisense RNA 1)

CTNS-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004937.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-3656727-G-A is Pathogenic according to our data. Variant chr17-3656727-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3656727-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNS	NM_004937.3 linkuse as main transcript	c.613G>A	p.Asp205Asn	missense_variant	9/12	ENST00000046640.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNS	ENST00000046640.9 linkuse as main transcript	c.613G>A	p.Asp205Asn	missense_variant	9/12	1	NM_004937.3	P1	O60931-1
CTNS-AS1	ENST00000575741.1 linkuse as main transcript	n.532+129C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151774

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251332

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151774

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74084

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystinosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2017	Variant summary: The CTNS c.613G>A (p.Asp205Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. Multiple studies confirmed that this variant is abolishing cysteine transport (Kalatzis_HMG_2004, Ruivo_PNAS_2011). The variant of interest has not been found in a large, broad control population, ExAC in 120966 control chromosomes and was found in gnomAD in 2/246212 at a frequency of 0.000008123 which does not exceed the estimated maximal expected allele frequency of a pathogenic CTNS variant (0.0025). This variant was reported in multiple patients with cystinosis, including 2 compound heterozigotes with CTNS p.S298N and 57 kb deletion, respectively and in one homozygote with osteogenesis imperfecta (Shotelersuk_AJHG_1998, Kalatzis_HMG_2004). In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Nephropathic cystinosis

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 08, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2023

Published functional studies demonstrate a damaging effect: abolished cystine transport (Kalatzis et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35571017, 28186126, 15128704, 34237326, Ghazi2017[casereport], 35513889, 20301574, 28793998, 30949462, 36113465, 28983406, 22528245, 9792862) -

Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 205 of the CTNS protein (p.Asp205Asn). This variant is present in population databases (rs113994208, gnomAD 0.003%). This missense change has been observed in individual(s) with cystinosis (PMID: 9792862, 22528245, 28983406). ClinVar contains an entry for this variant (Variation ID: 21440). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTNS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTNS function (PMID: 15128704, 22232659). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.10

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.5

H;H

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.95

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.99

MPC

0.65

ClinPred

0.99

GERP RS

4.9

Varity_R

0.63

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over