17-3656529-G-A

Position:

• chr17-3656529-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.823

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 257154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3656529-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.504G>A	p.Thr168Thr	synonymous_variant	8/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.504G>A	p.Thr168Thr	synonymous_variant	8/12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 21548 AN: 142748 Hom.: 2043 Cov.: 22

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

GnomAD3 exomes AF: 0.184 AC: 45835 AN: 249472 Hom.: 4481 AF XY: 0.183 AC XY: 24783 AN XY: 135122

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 SAS exome AF: 0.168

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.: 35 AF XY: 0.187 AC XY: 135920 AN XY: 726802

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.151 AC: 21565 AN: 142856 Hom.: 2048 Cov.: 22 AF XY: 0.153 AC XY: 10529 AN XY: 69028

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.163

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

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2017	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2018	- -

Ocular cystinosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Nephropathic cystinosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.2
DANN	Benign	0.87

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

LitVar

Other links and lift over

dbSNP: rs1800528; hg19: chr17-3559823; COSMIC: COSV50440774; COSMIC: COSV50440774;