rs786204632

Variant names:

• chr17-3658129-TCTC-T
• rs786204632
• NM_004937.3:c.809_811delCCT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_001031681.3(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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S270S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CTNS NM_001031681.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.33
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001031681.3. 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 Pathogenic. ClinVar VariationId is 189020.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031681.3. 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.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	Exon 10 of 12	NP_004928.2
	CTNS	NM_001031681.3		c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	Exon 10 of 13	NP_001026851.2
	CTNS	NM_001374492.1		c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	Exon 10 of 13	NP_001361421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	Exon 10 of 12	ENSP00000046640.4
	CTNS	ENST00000381870.8	TSL:1	c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	Exon 10 of 13	ENSP00000371294.3
	CTNS	ENST00000673965.1		c.809_811delCCT	p.Ser270del	disruptive_inframe_deletion	Exon 10 of 12	ENSP00000500995.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251220 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4470

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111936

Other (OTH) AF: 0.0000166 AC: 1 AN: 60240

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Nephropathic cystinosis (2)
1	-	-	Nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs786204632; hg19: chr17-3561423;