17-3658102-C-G

Position:

• chr17-3658102-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004937.3(CTNS):​c.779C>G​(p.Thr260Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T260I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 36)
• Consequence: CTNS NM_004937.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34269732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.779C>G	p.Thr260Ser	missense_variant	10/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.779C>G	p.Thr260Ser	missense_variant	10/12	1	NM_004937.3	ENSP00000046640	P1
CTNS-AS1	ENST00000575741.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.33	P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.28
Sift	Benign	0.12	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	B;P
Vest4		0.26
MutPred		0.28		Loss of glycosylation at T260 (P = 0.0537);Loss of glycosylation at T260 (P = 0.0537);
MVP		0.82
MPC		0.19
ClinPred		0.29	T
GERP RS		2.9
Varity_R		0.063
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs161400; hg19: chr17-3561396;