rs222753

Variant names:

• chr17-3660045-C-T
• rs222753
• NM_004937.3:c.970+70C>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+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,483,220 control chromosomes in the GnomAD database, including 136,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10596 hom., cov: 33)
  • Exomes 𝑓: 0.43 (125862 hom.)
• Consequence: CTNS NM_004937.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.489
• Publications: 7 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: ClinGen, Myriad Women’s Health
• nephropathic cystinosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• juvenile nephropathic cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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=-0.82).
• BP6: Variant 17-3660045-C-T is Benign according to our data. Variant chr17-3660045-C-T is described in ClinVar as Benign. ClinVar VariationId is 1184687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004937.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	NM_004937.3	MANE Select	c.970+70C>T		intron	N/A	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.970+70C>T		intron	N/A	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.970+70C>T		intron	N/A	NP_001361421.1	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.970+70C>T		intron	N/A	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.970+70C>T		intron	N/A	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.970+70C>T		intron	N/A	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52608 AN: 152010 Hom.: 10601 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.379

GnomAD4 exome AF: 0.427 AC: 567767 AN: 1331092 Hom.: 125862 Cov.: 20 AF XY: 0.425 AC XY: 283719 AN XY: 668012

African (AFR) AF: 0.131 AC: 4043 AN: 30894

American (AMR) AF: 0.347 AC: 15382 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 9722 AN: 25126

East Asian (EAS) AF: 0.213 AC: 8329 AN: 39028

South Asian (SAS) AF: 0.327 AC: 27271 AN: 83418

European-Finnish (FIN) AF: 0.468 AC: 24108 AN: 51560

Middle Eastern (MID) AF: 0.364 AC: 1445 AN: 3974

European-Non Finnish (NFE) AF: 0.457 AC: 455744 AN: 997086

Other (OTH) AF: 0.390 AC: 21723 AN: 55720

GnomAD4 genome AF: 0.346 AC: 52601 AN: 152128 Hom.: 10596 Cov.: 33 AF XY: 0.345 AC XY: 25649 AN XY: 74384

African (AFR) AF: 0.148 AC: 6142 AN: 41542

American (AMR) AF: 0.369 AC: 5640 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1331 AN: 3468

East Asian (EAS) AF: 0.180 AC: 929 AN: 5156

South Asian (SAS) AF: 0.321 AC: 1547 AN: 4826

European-Finnish (FIN) AF: 0.472 AC: 5000 AN: 10596

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30768 AN: 67928

Other (OTH) AF: 0.373 AC: 789 AN: 2114

Alfa AF: 0.393 Hom.: 1572

Bravo AF: 0.329

Asia WGS AF: 0.238 AC: 831 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephropathic cystinosis (2)
-	-	2	not provided (2)
-	-	1	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		-0.49
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: rs222753; hg19: chr17-3563339; COSMIC: COSV50440606; COSMIC: COSV50440606;