ENST00000381870.8:c.-335C>T

Variant names:

• chr17-3636603-C-T
• rs11657606
• ENST00000381870.8:c.-335C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000381870.8(CTNS):​c.-335C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0639 in 211,556 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (291 hom., cov: 33)
  • Exomes 𝑓: 0.073 (187 hom.)
• Consequence: CTNS ENST00000381870.8 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.579
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-3636603-C-T is Benign according to our data. Variant chr17-3636603-C-T is described in ClinVar as Benign. ClinVar VariationId is 322818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381870.8. 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_001031681.3		c.-335C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_001026851.2	O60931-2
	CTNS	NM_001031681.3		c.-335C>T		5_prime_UTR	Exon 1 of 13	NP_001026851.2	O60931-2
	CTNS	NM_004937.3	MANE Select	c.-458C>T		upstream_gene	N/A	NP_004928.2	O60931-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000381870.8	TSL:1	c.-335C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000381870.8	TSL:1	c.-335C>T		5_prime_UTR	Exon 1 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.-330C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes AF: 0.0604 AC: 9199 AN: 152228 Hom.: 287 Cov.: 33

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.0643

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0728

Gnomad OTH AF: 0.0573

GnomAD4 exome AF: 0.0726 AC: 4296 AN: 59210 Hom.: 187 Cov.: 0 AF XY: 0.0716 AC XY: 2200 AN XY: 30742

African (AFR) AF: 0.0443 AC: 83 AN: 1872

American (AMR) AF: 0.0566 AC: 82 AN: 1450

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 231 AN: 2330

East Asian (EAS) AF: 0.000238 AC: 1 AN: 4196

South Asian (SAS) AF: 0.0877 AC: 374 AN: 4264

European-Finnish (FIN) AF: 0.0698 AC: 249 AN: 3566

Middle Eastern (MID) AF: 0.120 AC: 37 AN: 308

European-Non Finnish (NFE) AF: 0.0786 AC: 2933 AN: 37296

Other (OTH) AF: 0.0779 AC: 306 AN: 3928

GnomAD4 genome AF: 0.0605 AC: 9223 AN: 152346 Hom.: 291 Cov.: 33 AF XY: 0.0596 AC XY: 4442 AN XY: 74490

African (AFR) AF: 0.0440 AC: 1830 AN: 41586

American (AMR) AF: 0.0491 AC: 751 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.0818 AC: 395 AN: 4830

European-Finnish (FIN) AF: 0.0643 AC: 683 AN: 10620

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0728 AC: 4954 AN: 68024

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0676 Hom.: 458

Bravo AF: 0.0578

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephropathic cystinosis (1)
-	-	1	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.7
DANN	Benign	0.83
PhyloP100		-0.58
PromoterAI		0.0083	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11657606; hg19: chr17-3539897;