rs76153698

Variant names:

• chr17-3659990-G-A
• rs76153698
• NM_004937.3:c.970+15G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-3659990-G-A
• chr17-3659990-G-C
• chr17-3659990-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004937.3(CTNS):​c.970+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,596,700 control chromosomes in the GnomAD database, including 468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (135 hom., cov: 34)
  • Exomes 𝑓: 0.019 (333 hom.)
• Consequence: CTNS NM_004937.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.27
• Publications: 3 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-3659990-G-A is Benign according to our data. Variant chr17-3659990-G-A is described in ClinVar as [Benign]. Clinvar id is 257158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNS	NM_004937.3	c.970+15G>A		intron_variant	Intron 11 of 11	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.970+15G>A		intron_variant	Intron 11 of 11	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4852 AN: 152198 Hom.: 134 Cov.: 34

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0201 AC: 5034 AN: 250196 AF XY: 0.0195

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0305

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0186 AC: 26850 AN: 1444384 Hom.: 333 Cov.: 29 AF XY: 0.0184 AC XY: 13235 AN XY: 719412

African (AFR) AF: 0.0696 AC: 2306 AN: 33134

American (AMR) AF: 0.0109 AC: 487 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 443 AN: 26026

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39638

South Asian (SAS) AF: 0.0208 AC: 1785 AN: 85932

European-Finnish (FIN) AF: 0.0303 AC: 1601 AN: 52800

Middle Eastern (MID) AF: 0.0154 AC: 80 AN: 5192

European-Non Finnish (NFE) AF: 0.0171 AC: 18765 AN: 1097174

Other (OTH) AF: 0.0230 AC: 1378 AN: 59798

GnomAD4 genome AF: 0.0319 AC: 4857 AN: 152316 Hom.: 135 Cov.: 34 AF XY: 0.0317 AC XY: 2360 AN XY: 74480

African (AFR) AF: 0.0706 AC: 2934 AN: 41578

American (AMR) AF: 0.0145 AC: 222 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4824

European-Finnish (FIN) AF: 0.0309 AC: 328 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1100 AN: 68016

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0233 Hom.: 17

Bravo AF: 0.0321

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CTNS c.970+15G>A variant involves the alteration of a non-conserved intronic nucleotide at a position not widely known to affect gene splicing. Mutation taster predicts a benign outcome for this variant. This variant was found in 2496/120078 control chromosomes (45 homozygotes) from ExAC at a frequency of 0.0207865, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic CTNS variant (0.0025), suggesting this variant is likely a benign polymorphism. It is more common in African subpopulation with an allele frequency of 6.5% (674/10238 chromosomes). This variant was found in a cystinosis patient who carried c.140+1G>T in homozygous state, further supporting benign outcome of the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ocular cystinosis Benign:1

Jan 13, 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. -

Nephropathic cystinosis Benign:1

Jan 13, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.027
DANN	Benign	0.89
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76153698; hg19: chr17-3563284;