rs117404824

chr17-3647490-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004937.3(CTNS):c.108C>T(p.Asn36=) variant causes a synonymous 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_004937.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.03

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]

LOC105371493 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 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 [Likely_benign]. Clinvar id is 322835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNS	NM_004937.3	c.108C>T	p.Asn36=	synonymous_variant	4/12	ENST00000046640.9
LOC105371493	XR_007065579.1	n.1935-2315G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNS	ENST00000046640.9	c.108C>T	p.Asn36=	synonymous_variant	4/12	1	NM_004937.3	P1

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

GnomAD3 exomes AF: 0.00706 AC: 1775 AN: 251418 Hom.: 23 AF XY: 0.00697 AC XY: 947 AN XY: 135902

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 SAS 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

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.00929

Gnomad4 OTH exome AF: 0.00550

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

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.00830

Gnomad4 OTH AF: 0.00284

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CTNS: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 04, 2020

- -

Ocular cystinosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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

Invitae

Jan 29, 2024

- -

Cystinosis Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.3
Dann	Benign	0.56

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

LitVar

Other links and lift over

dbSNP: rs117404824; hg19: chr17-3550784;