rs1555561048

Variant names:

• chr17-3648929-GAAGT-G
• rs1555561048
• NM_004937.3:c.225+5_225+8delGTAA

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The ENST00000046640.9(CTNS):​c.224_225+2delAAGT​(p.Glu75ValfsTer7) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003443723: Studies have shown that this variant results in skipping of exons 4 and 5 , and produces a non-functional protein and/or introduces a premature termination codon (PMID:12442267).". Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNS ENST00000046640.9 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 6.35
• Publications: 0 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

LOC105371493 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003443723: Studies have shown that this variant results in skipping of exons 4 and 5 , and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12442267).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3648929-GAAGT-G is Pathogenic according to our data. Variant chr17-3648929-GAAGT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 550829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000046640.9. 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.225+5_225+8delGTAA		splice_region intron	N/A	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.225+5_225+8delGTAA		splice_region intron	N/A	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.225+5_225+8delGTAA		splice_region 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.224_225+2delAAGT	p.Glu75ValfsTer7	frameshift splice_donor splice_region intron	Exon 5 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.224_225+2delAAGT	p.Glu75ValfsTer7	frameshift splice_donor splice_region intron	Exon 5 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000488623.6	TSL:3	c.-504_-503+2delAAGT		splice_region	Exon 4 of 11	ENSP00000501016.1	A0A669KAZ5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 2

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

Other links and lift over

dbSNP: rs1555561048; hg19: chr17-3552223;