Genetic Variant NM_004937.3:c.206_210delTCCTT (chr17-3648911-ATCCTT-A) – ACMG Classification: Pathogenic (22 pts)

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_004937.3(CTNS):c.206_210delTCCTT(p.Ile69ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000186 in 1,613,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005339637: "In vitro functional studies using cultured patient fibroblasts hemizygous for the p.Ile69Argfs*5 variant (with a 57 kb deletion of CTNS exons 1-10 on the opposite allele) detected an approximately 10X increase of intracellular cysteine in patient fibroblasts relative to wild type." PMID:20061170" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. I69I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CTNS
NM_004937.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.11

Publications

1 publications found

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 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

CTNS links:

LOC105371493 (HGNC:):

LOC105371493 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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: SCV005339637: "In vitro functional studies using cultured patient fibroblasts hemizygous for the p.Ile69Argfs*5 variant (with a 57 kb deletion of CTNS exons 1-10 on the opposite allele) detected an approximately 10X increase of intracellular cysteine in patient fibroblasts relative to wild type." PMID:20061170; SCV001554609: Fibroblasts from this patient were assessed as having higher levels of intracellular cystine compared to normal controls (e.g. Vitcitsky_2010).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-3648911-ATCCTT-A is Pathogenic according to our data. Variant chr17-3648911-ATCCTT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 455787.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNS	NM_004937.3	MANE Select	c.206_210delTCCTT	p.Ile69ArgfsTer5	frameshift	Exon 5 of 12	NP_004928.2	O60931-1
CTNS	NM_001031681.3		c.206_210delTCCTT	p.Ile69ArgfsTer5	frameshift	Exon 5 of 13	NP_001026851.2	O60931-2
CTNS	NM_001374492.1		c.206_210delTCCTT	p.Ile69ArgfsTer5	frameshift	Exon 5 of 13	NP_001361421.1	O60931-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNS	ENST00000046640.9	TSL:1 MANE Select	c.206_210delTCCTT	p.Ile69ArgfsTer5	frameshift	Exon 5 of 12	ENSP00000046640.4	O60931-1
CTNS	ENST00000381870.8	TSL:1	c.206_210delTCCTT	p.Ile69ArgfsTer5	frameshift	Exon 5 of 13	ENSP00000371294.3	O60931-2
CTNS	ENST00000673965.1		c.206_210delTCCTT	p.Ile69ArgfsTer5	frameshift	Exon 5 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460968

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111172

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nephropathic cystinosis (2)

CTNS-related disorder (1)

Cystinosis (1)

Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)

Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over