rs113994211

chr17-3656572-GTGCCCTACATCAAGGTACGGCCTTGCC-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_004937.3(CTNS):c.559_561+24del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,610,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

CTNS
NM_004937.3 splice_donor, splice_donor_5th_base, coding_sequence, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.75

Variant links:

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 links:

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

CTNS-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 17-3656572-GTGCCCTACATCAAGGTACGGCCTTGCC-G is Pathogenic according to our data. Variant chr17-3656572-GTGCCCTACATCAAGGTACGGCCTTGCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNS	NM_004937.3 linkuse as main transcript	c.559_561+24del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/12	ENST00000046640.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNS	ENST00000046640.9 linkuse as main transcript	c.559_561+24del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/12	1	NM_004937.3	P1	O60931-1
CTNS-AS1	ENST00000575741.1 linkuse as main transcript	n.532+257_532+283del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000201

AC:

AN:

149270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250720

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135752

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461684

Hom.:

AF XY:

0.0000481

AC XY:

AN XY:

727130

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000201

AC:

AN:

149270

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72724

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000445

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephropathic cystinosis

Pathogenic:3

Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 15, 2015	- -

Infantile nephropathic cystinosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Mar 07, 2022

- -

Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This variant results in the deletion of part of exon 8 of the CTNS gene. RNA analysis indicates that a similar copy number variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs771633120, gnomAD 0.008%). A similar copy number variant has been observed in individual(s) with infantile cystinosis (PMID: 11562417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 898‚Äì900_x0001_+24del27 . ClinVar contains an entry for this variant (Variation ID: 21442). Studies have shown that a similar copy number variant results in multiple aberrant spliced transcripts and introduces a premature termination codon (PMID: 11562417). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Cystinosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Mar 12, 2018

This individual is heterozygous for the c.559_561+24del variant in the CTNS gene. This variant has been previously reported multiple times, as 898-900_24del27, in the literature as a known founder mutation, originating in Brittany, France. This deletion has been shown to abolish the splice donor consensus site of CTNS exon 8, resulting in aberrant transcript splicing (Kalatzis et al J Am Soc Nephrol 2001 (12):2170-2174; Attard et al Hum Mol Genetics 1999 8(13):2507-2514). This variant is considered to be pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over