Genetic Variant CTNS:p.Tyr173Cys (chr17-3656543-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_004937.3(CTNS):c.518A>G(p.Tyr173Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y173H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 27)

Failed GnomAD Quality Control

Consequence

CTNS
NM_004937.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 8.57

Publications

3 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 links:

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

CTNS-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004937.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-3656542-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2925594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 17-3656543-A-G is Pathogenic according to our data. Variant chr17-3656543-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 558561.Status of the report is criteria_provided_single_submitter, 1 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.518A>G	p.Tyr173Cys	missense	Exon 8 of 12	NP_004928.2	O60931-1
CTNS	NM_001031681.3		c.518A>G	p.Tyr173Cys	missense	Exon 8 of 13	NP_001026851.2	O60931-2
CTNS	NM_001374492.1		c.518A>G	p.Tyr173Cys	missense	Exon 8 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.518A>G	p.Tyr173Cys	missense	Exon 8 of 12	ENSP00000046640.4	O60931-1
CTNS	ENST00000381870.8	TSL:1	c.518A>G	p.Tyr173Cys	missense	Exon 8 of 13	ENSP00000371294.3	O60931-2
CTNS	ENST00000488623.6	TSL:3	c.-236A>G		5_prime_UTR_premature_start_codon_gain	Exon 7 of 11	ENSP00000501016.1	A0A669KAZ5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

145888

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

145888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70804

African (AFR)

AF:

0.00

AC:

AN:

38824

American (AMR)

AF:

0.00

AC:

AN:

14380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

4944

South Asian (SAS)

AF:

0.00

AC:

AN:

4414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66766

Other (OTH)

AF:

0.00

AC:

AN:

1982

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Nephropathic cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PhyloP100

8.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-8.5

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.72

Loss of sheet (P = 0.0084)

MVP

0.99

MPC

0.76

ClinPred

1.0

GERP RS

4.8

Varity_R

0.96

gMVP

0.95

Mutation Taster

=0/100

disease causing

(source)

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

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