17-3658102-C-T

Variant names:

• chr17-3658102-C-T
• rs161400
• NM_004937.3:c.779C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004937.3(CTNS):​c.779C>T​(p.Thr260Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 1,612,378 control chromosomes in the GnomAD database, including 714,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T260S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.85 (57374 hom., cov: 36)
  • Exomes 𝑓: 0.95 (656869 hom.)
• Consequence: CTNS NM_004937.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.40
• Publications: 42 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-AS1 (HGNC:56090): (CTNS antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.166222E-7).
• BP6: Variant 17-3658102-C-T is Benign according to our data. Variant chr17-3658102-C-T is described in ClinVar as Benign. ClinVar VariationId is 257157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004937.3. 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.779C>T	p.Thr260Ile	missense	Exon 10 of 12	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.779C>T	p.Thr260Ile	missense	Exon 10 of 13	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.779C>T	p.Thr260Ile	missense	Exon 10 of 13	NP_001361421.1	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.779C>T	p.Thr260Ile	missense	Exon 10 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.779C>T	p.Thr260Ile	missense	Exon 10 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.779C>T	p.Thr260Ile	missense	Exon 10 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes AF: 0.854 AC: 129984 AN: 152144 Hom.: 57356 Cov.: 36

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.916

Gnomad FIN AF: 0.970

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.958

Gnomad OTH AF: 0.879

GnomAD2 exomes AF: 0.926 AC: 232591 AN: 251286 AF XY: 0.931

Gnomad AFR exome AF: 0.589

Gnomad AMR exome AF: 0.957

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.934

Gnomad FIN exome AF: 0.967

Gnomad NFE exome AF: 0.957

Gnomad OTH exome AF: 0.932

GnomAD4 exome AF: 0.946 AC: 1381984 AN: 1460116 Hom.: 656869 Cov.: 66 AF XY: 0.947 AC XY: 687635 AN XY: 726414

African (AFR) AF: 0.578 AC: 19302 AN: 33422

American (AMR) AF: 0.952 AC: 42558 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 23652 AN: 26130

East Asian (EAS) AF: 0.937 AC: 37213 AN: 39696

South Asian (SAS) AF: 0.919 AC: 79184 AN: 86188

European-Finnish (FIN) AF: 0.967 AC: 51518 AN: 53290

Middle Eastern (MID) AF: 0.893 AC: 3997 AN: 4478

European-Non Finnish (NFE) AF: 0.961 AC: 1068824 AN: 1111946

Other (OTH) AF: 0.925 AC: 55736 AN: 60244

GnomAD4 genome AF: 0.854 AC: 130050 AN: 152262 Hom.: 57374 Cov.: 36 AF XY: 0.858 AC XY: 63901 AN XY: 74458

African (AFR) AF: 0.607 AC: 25185 AN: 41514

American (AMR) AF: 0.919 AC: 14072 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3138 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4850 AN: 5172

South Asian (SAS) AF: 0.916 AC: 4425 AN: 4832

European-Finnish (FIN) AF: 0.970 AC: 10304 AN: 10628

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.958 AC: 65163 AN: 68018

Other (OTH) AF: 0.876 AC: 1853 AN: 2116

Alfa AF: 0.913 Hom.: 133500

Bravo AF: 0.837

TwinsUK AF: 0.955 AC: 3542

ALSPAC AF: 0.958 AC: 3691

ESP6500AA AF: 0.599 AC: 2641

ESP6500EA AF: 0.956 AC: 8218

ExAC AF: 0.918 AC: 111468

Asia WGS AF: 0.906 AC: 3151 AN: 3478

EpiCase AF: 0.954

EpiControl AF: 0.953

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Nephropathic cystinosis (2)
-	-	2	Ocular cystinosis (2)
-	-	1	Cystinosis (1)
-	-	1	Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.4
DANN	Benign	0.84
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	6.2e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.57	N
PhyloP100		2.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	3.1	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.17
ClinPred		0.0049	T
GERP RS		2.9
Varity_R		0.038
gMVP		0.45
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs161400; hg19: chr17-3561396; COSMIC: COSV107218388; COSMIC: COSV107218388;