rs786204632

Positions:

• chr17-3658129-TCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_004937.3(CTNS):​c.809_811delCCT​(p.Ser270del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CTNS NM_004937.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.33

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-AS1 (HGNC:56090): (CTNS antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a domain PQ-loop 2 (size 65) in uniprot entity CTNS_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_004937.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004937.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-3658129-TCTC-T is Pathogenic according to our data. Variant chr17-3658129-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	10/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	10/12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251220 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460086 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephropathic cystinosis Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2022	- -

Nephrotic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs786204632; hg19: chr17-3561423;