17-3656487-T-C

Position:

chr17-3656487-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004937.3(CTNS):c.462T>C(p.Ser154=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,587,498 control chromosomes in the GnomAD database, including 1,608 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 Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 702 hom., cov: 17)

Exomes 𝑓: 0.0078 ( 906 hom. )

Consequence

CTNS
NM_004937.3 splice_region, synonymous

Scores

Splicing: ADA: 0.00006894

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 17-3656487-T-C is Benign according to our data. Variant chr17-3656487-T-C is described in ClinVar as [Benign]. Clinvar id is 257153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3656487-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3 linkuse as main transcript	c.462T>C	p.Ser154=	splice_region_variant, synonymous_variant	8/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9 linkuse as main transcript	c.462T>C	p.Ser154=	splice_region_variant, synonymous_variant	8/12	1	NM_004937.3	ENSP00000046640	P1	O60931-1
CTNS-AS1	ENST00000575741.1 linkuse as main transcript	n.532+369A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0496

AC:

6421

AN:

129490

Hom.:

694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00150

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00654

Gnomad NFE

AF:

0.000710

Gnomad OTH

AF:

0.0327

GnomAD3 exomes

AF:

0.0186

AC:

4545

AN:

244426

Hom.:

374

AF XY:

0.0156

AC XY:

2070

AN XY:

132416

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.00958

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000772

Gnomad SAS exome

AF:

0.0236

Gnomad FIN exome

AF:

0.0000482

Gnomad NFE exome

AF:

0.000707

Gnomad OTH exome

AF:

0.00786

GnomAD4 exome

AF:

0.00783

AC:

11420

AN:

1457914

Hom.:

906

Cov.:

AF XY:

0.00765

AC XY:

5543

AN XY:

725042

show subpopulations

Gnomad4 AFR exome

AF:

0.222

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00121

Gnomad4 SAS exome

AF:

0.0233

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000511

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

AF:

0.0498

AC:

6455

AN:

129584

Hom.:

702

Cov.:

AF XY:

0.0496

AC XY:

3078

AN XY:

62074

show subpopulations

Gnomad4 AFR

AF:

0.194

Gnomad4 AMR

AF:

0.0197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00151

Gnomad4 SAS

AF:

0.0193

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000710

Gnomad4 OTH

AF:

0.0323

Alfa

AF:

0.0104

Hom.:

154

Bravo

AF:

0.0702

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2017	Variant summary: The CTNS c.462T>C (p.Ser154Ser) variant involves the alteration of the first nucleotide (non-conserved) in exon 8, resulting in a synonymous change. Mutation Taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 2595/81038 control chromosomes (including 211 homozygotes) at a frequency of 0.032022, which is approximately 13 times the estimated maximal expected allele frequency of a pathogenic CTNS variant (0.0025), thus it is a benign polymorphism. The variant is more common in African subpopulation with an allele frequency of 0.2601 (2065/7938 chromosomes). In addition, multiple clinical diagnostic laboratories have classified this variant as likely benign/benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Ocular cystinosis

Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephropathic cystinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

-0.60

CADD

Benign

4.5

DANN

Benign

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000069

dbscSNV1_RF

Benign

0.012

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over