rs35086888

Positions:

chr17-3647506-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004937.3(CTNS):c.124G>A(p.Val42Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,614,070 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 79 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 88 hom. )

Consequence

CTNS
NM_004937.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12

Conservation

PhyloP100: 0.865

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 (HGNC:):

CTNS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021084845).

BP6

Variant 17-3647506-G-A is Benign according to our data. Variant chr17-3647506-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 4447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3647506-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant	4/12	ENST00000046640.9	NP_004928.2	O60931-1A0A0S2Z3K3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant	4/12	1	NM_004937.3	ENSP00000046640.4		O60931-1

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2585

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0598

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.00444

AC:

1115

AN:

251340

Hom.:

AF XY:

0.00331

AC XY:

450

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0613

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00182

AC:

2662

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1125

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0662

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000510

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000603

Gnomad4 OTH exome

AF:

0.00351

GnomAD4 genome

AF:

0.0170

AC:

2591

AN:

152288

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1224

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0597

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.00415

Hom.:

Bravo

AF:

0.0194

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0574

AC:

253

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00544

AC:

660

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2019	This variant is associated with the following publications: (PMID: 15128704, 10556299, 20981092, 24123366) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nephropathic cystinosis

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Cystinosis, atypical nephropathic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1999

- -

CTNS-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ocular cystinosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cystinosis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.090

CADD

Benign

4.5

DANN

Uncertain

0.97

DEOGEN2

Benign

0.24

T;.;.;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.78

T;T;T;T;T

MetaRNN

Benign

0.021

T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.93

L;L;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

0.060

N;N;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.49

T;T;T;T;.

Sift4G

Benign

0.69

T;T;T;T;T

Polyphen

0.0090

B;B;.;.;.

Vest4

0.13

MVP

0.78

MPC

0.13

ClinPred

0.0054

GERP RS

3.0

Varity_R

0.018

gMVP

0.27

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

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