rs76153698

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr17-3659990-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.970+15G>A		intron_variant		ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.970+15G>A		intron_variant		1	NM_004937.3	ENSP00000046640	P1

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

GnomAD3 exomes AF: 0.0201 AC: 5034 AN: 250196 Hom.: 94 AF XY: 0.0195 AC XY: 2643 AN XY: 135520

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 SAS exome AF: 0.0209

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

Gnomad4 AFR exome AF: 0.0696

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0230

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

Gnomad4 AFR AF: 0.0706

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0240 Hom.: 11

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2017	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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ocular cystinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Nephropathic cystinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.027
DANN	Benign	0.89

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

Other links and lift over

dbSNP: rs76153698; hg19: chr17-3563284;