17-3647490-C-T

Variant names:

• chr17-3647490-C-T
• rs117404824
• NM_004937.3:c.108C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374493.1(CTNS):​c.-249C>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 0.00801 in 1,614,108 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (103 hom.)
• Consequence: CTNS NM_001374493.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.03
• Publications: 1 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

LOC105371493 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 17-3647490-C-T is Benign according to our data. Variant chr17-3647490-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 322835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0063 (959/152298) while in subpopulation NFE AF = 0.0083 (565/68032). AF 95% confidence interval is 0.00774. There are 13 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374493.1. 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_004937.3	MANE Select	c.108C>T	p.Asn36Asn	synonymous	Exon 4 of 12	NP_004928.2	O60931-1
	CTNS	NM_001374493.1		c.-249C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 11	NP_001361422.1	A0A669KB82
	CTNS	NM_001374494.1		c.-334C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001361423.1	A0A669KB82

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.108C>T	p.Asn36Asn	synonymous	Exon 4 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.108C>T	p.Asn36Asn	synonymous	Exon 4 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673669.1		c.-249C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000501123.1	A0A669KB82

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 959 AN: 152180 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00830

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00706 AC: 1775 AN: 251418 AF XY: 0.00697

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00819 AC: 11969 AN: 1461810 Hom.: 103 Cov.: 31 AF XY: 0.00787 AC XY: 5724 AN XY: 727216

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0215 AC: 1149 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00929 AC: 10330 AN: 1111978

Other (OTH) AF: 0.00550 AC: 332 AN: 60396

GnomAD4 genome AF: 0.00630 AC: 959 AN: 152298 Hom.: 13 Cov.: 33 AF XY: 0.00682 AC XY: 508 AN XY: 74458

African (AFR) AF: 0.00142 AC: 59 AN: 41564

American (AMR) AF: 0.00144 AC: 22 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00830 AC: 565 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00728 Hom.: 14

Bravo AF: 0.00473

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00693

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cystinosis (1)
-	-	1	Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)
-	-	1	Nephropathic cystinosis (1)
-	-	1	not specified (1)
-	-	1	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs117404824; hg19: chr17-3550784;