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rs77453839

chr17-3656487-T-Cchr17-3656487-T-G

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

2
Splicing: ADA: 0.00006894
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

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

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.32 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
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 UniProt
CTNSNM_004937.3 linkuse as main transcriptc.462T>C p.Ser154= splice_region_variant, synonymous_variant 8/12 ENST00000046640.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CTNSENST00000046640.9 linkuse as main transcriptc.462T>C p.Ser154= splice_region_variant, synonymous_variant 8/121 NM_004937.3 P1O60931-1
CTNS-AS1ENST00000575741.1 linkuse as main transcriptn.532+369A>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0496
AC:
6421
AN:
129490
Hom.:
694
Cov.:
17
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.:
32
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0498
AC:
6455
AN:
129584
Hom.:
702
Cov.:
17
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:
76
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 16, 2017Variant 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, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicSep 21, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 13, 2018This 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. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Ocular cystinosis Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Cystinosis Benign:1
Benign, no assertion criteria providedclinical testingNatera, 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.

Other links and lift over

dbSNP: rs77453839; hg19: chr17-3559781; API