rs1800528

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004937.3(CTNS):c.504G>A(p.Thr168Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,603,876 control chromosomes in the GnomAD database, including 28,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2048 hom., cov: 22)

Exomes 𝑓: 0.19 ( 26763 hom. )

Consequence

CTNS
NM_004937.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.823

Publications

18 publications found

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 was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 17-3656529-G-A is Benign according to our data. Variant chr17-3656529-G-A is described in ClinVar as Benign. ClinVar VariationId is 257154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.823 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNS	NM_004937.3 link	c.504G>A	p.Thr168Thr	synonymous_variant	Exon 8 of 12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9 link	c.504G>A	p.Thr168Thr	synonymous_variant	Exon 8 of 12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

21548

AN:

142748

Hom.:

2043

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0426

Gnomad AMI

AF:

0.0590

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.190

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.184

AC:

45835

AN:

249472

AF XY:

0.183

show subpopulations

Gnomad AFR exome

AF:

0.0385

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.202

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.188

AC:

274004

AN:

1461020

Hom.:

26763

Cov.:

AF XY:

0.187

AC XY:

135920

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.0357

AC:

1196

AN:

33466

American (AMR)

AF:

0.228

AC:

10163

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

3415

AN:

26134

East Asian (EAS)

AF:

0.177

AC:

7003

AN:

39660

South Asian (SAS)

AF:

0.167

AC:

14408

AN:

86200

European-Finnish (FIN)

AF:

0.236

AC:

12537

AN:

53202

Middle Eastern (MID)

AF:

0.180

AC:

1040

AN:

5768

European-Non Finnish (NFE)

AF:

0.192

AC:

213199

AN:

1111622

Other (OTH)

AF:

0.183

AC:

11043

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

13588

27176

40763

54351

67939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7424

14848

22272

29696

37120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.151

AC:

21565

AN:

142856

Hom.:

2048

Cov.:

AF XY:

0.153

AC XY:

10529

AN XY:

69028

show subpopulations

African (AFR)

AF:

0.0425

AC:

1617

AN:

38018

American (AMR)

AF:

0.194

AC:

2696

AN:

13910

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

423

AN:

3388

East Asian (EAS)

AF:

0.201

AC:

967

AN:

4816

South Asian (SAS)

AF:

0.168

AC:

715

AN:

4262

European-Finnish (FIN)

AF:

0.232

AC:

2190

AN:

9448

Middle Eastern (MID)

AF:

0.171

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.190

AC:

12540

AN:

65900

Other (OTH)

AF:

0.163

AC:

315

AN:

1930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

785

1570

2354

3139

3924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.165

Hom.:

1222

Bravo

AF:

0.145

Asia WGS

AF:

0.196

AC:

681

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 12, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr168Thr in exon 8 of CTNS: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 26.02% (1536/5904) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs1800528). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Ocular cystinosis

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephropathic cystinosis

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cystinosis

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

6.2

(source)

DANN

Benign

0.87

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over