rs113994206

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_004937.3(CTNS):c.473T>C(p.Leu158Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,598,042 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L158L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., cov: 19)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CTNS
NM_004937.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.99

Publications

11 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: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 17-3656498-T-C is Pathogenic according to our data. Variant chr17-3656498-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004937.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTNS	NM_004937.3	MANE Select	c.473T>C	p.Leu158Pro	missense	Exon 8 of 12	NP_004928.2
CTNS	NM_001031681.3		c.473T>C	p.Leu158Pro	missense	Exon 8 of 13	NP_001026851.2
CTNS	NM_001374492.1		c.473T>C	p.Leu158Pro	missense	Exon 8 of 13	NP_001361421.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTNS	ENST00000046640.9	TSL:1 MANE Select	c.473T>C	p.Leu158Pro	missense	Exon 8 of 12	ENSP00000046640.4
CTNS	ENST00000381870.8	TSL:1	c.473T>C	p.Leu158Pro	missense	Exon 8 of 13	ENSP00000371294.3
CTNS	ENST00000673965.1		c.473T>C	p.Leu158Pro	missense	Exon 8 of 12	ENSP00000500995.1

Frequencies

GnomAD3 genomes

AF:

0.0000435

AC:

AN:

137842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000561

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:

0.0000617

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

247434

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1460082

Hom.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

726218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.0000225

AC:

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000144

AC:

160

AN:

1111192

Other (OTH)

AF:

0.000166

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000435

AC:

AN:

137960

Hom.:

Cov.:

AF XY:

0.0000452

AC XY:

AN XY:

66398

show subpopulations

African (AFR)

AF:

0.0000559

AC:

AN:

35766

American (AMR)

AF:

0.00

AC:

AN:

13098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3350

East Asian (EAS)

AF:

0.00

AC:

AN:

4792

South Asian (SAS)

AF:

0.00

AC:

AN:

3904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000617

AC:

AN:

64834

Other (OTH)

AF:

0.00

AC:

AN:

1838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000118

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000742

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystinosis (2)

Nephropathic cystinosis (3)

not provided (2)

CTNS-related disorder (1)

Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)

Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

PhyloP100

6.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.99

MPC

0.87

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over