rs786204667

Variant names:

• chr17-3656585-AG-A
• rs786204667
• ENST00000046640.9:c.550delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004937.3(CTNS):​c.561+1delG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000205 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CTNS NM_004937.3 splice_donor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.59
• Publications: 1 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-AS1 (HGNC:56090): (CTNS antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6, offset of -1, new splice context is: caaGTacgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3656585-AG-A is Pathogenic according to our data. Variant chr17-3656585-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.561+1delG		splice_donor intron	N/A	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.561+1delG		splice_donor intron	N/A	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.561+1delG		splice_donor 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.550delG	p.Tyr185SerfsTer11	frameshift	Exon 8 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.550delG	p.Tyr185SerfsTer11	frameshift	Exon 8 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.550delG	p.Tyr185SerfsTer11	frameshift	Exon 8 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461496 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727044

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111814

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Nephropathic cystinosis (2)
1	-	-	Cystinosis (1)
1	-	-	Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)
1	-	-	Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: 0
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204667; hg19: chr17-3559879;