17-3656480-C-A

Position:

• chr17-3656480-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004937.3(CTNS):​c.462-7C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,585,604 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 16)
  • Exomes 𝑓: 0.0047 (28 hom.)
• Consequence: CTNS NM_004937.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005820
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0690

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-3656480-C-A is Benign according to our data. Variant chr17-3656480-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 288254.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 = 0.00334 (436/130356) while in subpopulation NFE AF= 0.00508 (321/63152). AF 95% confidence interval is 0.00462. There are 2 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 16. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.462-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.462-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004937.3	ENSP00000046640	P1
CTNS-AS1	ENST00000575741.1	n.532+376G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 436 AN: 130260 Hom.: 2 Cov.: 16

Gnomad AFR AF: 0.000842

Gnomad AMI AF: 0.00239

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00367

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00508

Gnomad OTH AF: 0.00177

GnomAD3 exomes AF: 0.00346 AC: 833 AN: 240820 Hom.: 0 AF XY: 0.00328 AC XY: 428 AN XY: 130480

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00381

Gnomad ASJ exome AF: 0.00204

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000676

Gnomad FIN exome AF: 0.00348

Gnomad NFE exome AF: 0.00532

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00472 AC: 6862 AN: 1455248 Hom.: 28 Cov.: 31 AF XY: 0.00461 AC XY: 3337 AN XY: 723604

Gnomad4 AFR exome AF: 0.000931

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.00365

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00425

GnomAD4 genome AF: 0.00334 AC: 436 AN: 130356 Hom.: 2 Cov.: 16 AF XY: 0.00291 AC XY: 181 AN XY: 62246

Gnomad4 AFR AF: 0.000839

Gnomad4 AMR AF: 0.00365

Gnomad4 ASJ AF: 0.00367

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00508

Gnomad4 OTH AF: 0.00175

Alfa AF: 0.00363 Hom.: 0

Bravo AF: 0.00368

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CTNS: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 19, 2016

- -

CTNS-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ocular cystinosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nephropathic cystinosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cystinosis Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs189632527; hg19: chr17-3559774;