Variant NM_004937.3:c.771_793delGGGAGTGACCACGTGGCTGCAGT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004937.3(CTNS):c.771_793delGGGAGTGACCACGTGGCTGCAGT(p.Gly258SerfsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CTNS
NM_004937.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.44

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-3658081-TCGTGGCTGCAGTGGGAGTGACCA-T is Pathogenic according to our data. Variant chr17-3658081-TCGTGGCTGCAGTGGGAGTGACCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 496276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNS	NM_004937.3 link	c.771_793delGGGAGTGACCACGTGGCTGCAGT	p.Gly258SerfsTer30	frameshift_variant	Exon 10 of 12	ENST00000046640.9	NP_004928.2	O60931-1A0A0S2Z3K3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9 link	c.771_793delGGGAGTGACCACGTGGCTGCAGT	p.Gly258SerfsTer30	frameshift_variant	Exon 10 of 12	1	NM_004937.3	ENSP00000046640.4		O60931-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251296

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460070

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

726384

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephropathic cystinosis

Pathogenic:5

Apr 26, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 23 bp deletion in CTNS has been previously reported in individuals with nephropathic cystinosis. This CTNS variant (rs759623796) is rare (<0.1%) in a large population dataset (gnomAD: 7/251296 total alleles; 0.003%; no homozygotes) and there is an entry in ClinVar. This frameshift variant results in a premature stop codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. -

Aug 16, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 25, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed frameshift c.771_793del (p.Gly258SerfsTer30) variant in CTNS gene has been reported in homozygous state in individual(s) affected with cystinosis (Chkioua L et al., 2015; Ghazi F, et. al., 2017). The p.Gly258SerfsTer30 variant is present with allele frequency 0.003% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Glycine 258, changes this amino acid to Serine residue, and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Gly258SerfsTer30. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in CTNS are known to be pathogenic (Elmonem MA, et. al., 2016). For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystinosis

Pathogenic:3

Jan 26, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant results in the deletion of a 23 nucleotides leading to a termination codon at position 288 of CTNS. The variant was present at a low frequency in the large and broad cohorts of the ExAC project (3/121,076 chromosomes) while it was observed in multiple CTNS patients in the literature. Considering all evidence, the variant was classified as pathogenic. -

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 02, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly258Serfs*30) in the CTNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNS are known to be pathogenic (PMID: 9537412, 27102039). This variant is present in population databases (rs759623796, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with cystinosis (PMID: 10556299, 26266097). This variant is also known as c.1109_1131del23. ClinVar contains an entry for this variant (Variation ID: 496276). For these reasons, this variant has been classified as Pathogenic. -

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