17-3660669-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000381870.8(CTNS):c.1138C>G(p.Pro380Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,518 control chromosomes in the GnomAD database, including 53,928 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 4011 hom., cov: 34)

Exomes 𝑓: 0.25 ( 49917 hom. )

Consequence

CTNS
ENST00000381870.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.224

Publications

24 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 Gene-Disease associations (from GenCC):

cystinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
nephropathic cystinosis
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P
juvenile nephropathic cystinosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
ocular cystinosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
nephropathic infantile cystinosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CTNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4540553E-4).

BP6

Variant 17-3660669-C-G is Benign according to our data. Variant chr17-3660669-C-G is described in ClinVar as Benign. ClinVar VariationId is 257152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNS	NM_004937.3 link	c.*300C>G		3_prime_UTR_variant	Exon 12 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.*300C>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30767

AN:

152164

Hom.:

4015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0475

Gnomad AMI

AF:

0.238

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.508

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.260

AC:

65181

AN:

251162

AF XY:

0.258

show subpopulations

Gnomad AFR exome

AF:

0.0422

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.514

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.249

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.254

AC:

371558

AN:

1461236

Hom.:

49917

Cov.:

AF XY:

0.254

AC XY:

184552

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.0368

AC:

1232

AN:

33480

American (AMR)

AF:

0.310

AC:

13868

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

7196

AN:

26136

East Asian (EAS)

AF:

0.473

AC:

18782

AN:

39700

South Asian (SAS)

AF:

0.227

AC:

19603

AN:

86258

European-Finnish (FIN)

AF:

0.212

AC:

11208

AN:

52786

Middle Eastern (MID)

AF:

0.180

AC:

1041

AN:

5768

European-Non Finnish (NFE)

AF:

0.255

AC:

283367

AN:

1111998

Other (OTH)

AF:

0.253

AC:

15261

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

18263

36527

54790

73054

91317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9666

19332

28998

38664

48330

<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:

0.202

AC:

30761

AN:

152282

Hom.:

4011

Cov.:

AF XY:

0.203

AC XY:

15137

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0473

AC:

1968

AN:

41584

American (AMR)

AF:

0.264

AC:

4043

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

970

AN:

3470

East Asian (EAS)

AF:

0.507

AC:

2616

AN:

5162

South Asian (SAS)

AF:

0.227

AC:

1098

AN:

4830

European-Finnish (FIN)

AF:

0.209

AC:

2218

AN:

10614

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.252

AC:

17129

AN:

67998

Other (OTH)

AF:

0.207

AC:

437

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1245

2490

3735

4980

6225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.236

Hom.:

1462

Bravo

AF:

0.202

TwinsUK

AF:

0.258

AC:

958

ALSPAC

AF:

0.251

AC:

966

ESP6500AA

AF:

0.0538

AC:

237

ESP6500EA

AF:

0.260

AC:

2240

ExAC

AF:

0.251

AC:

30440

Asia WGS

AF:

0.308

AC:

1071

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.252

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

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.Pro380Ala in exon 13 of CTNS: This variant is not expected to have clinical si gnificance because it has been identified in 49.67% (4271/8598) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2873624). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.4

(source)

DANN

Benign

0.55

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.47

MetaRNN

Benign

0.00015

MetaSVM

Benign

-1.0

PhyloP100

0.22

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.090

REVEL

Benign

0.15

Sift

Benign

0.78

Sift4G

Benign

1.0

Polyphen

0.0060

Vest4

0.028

MPC

0.16

ClinPred

0.00047

GERP RS

1.4

gMVP

0.57

Mutation Taster

=98/2

polymorphism (auto)

(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

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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