17-3656512-G-C

Variant names:

• chr17-3656512-G-C
• rs200818208
• NM_004937.3:c.487G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_004937.3(CTNS):​c.487G>C​(p.Val163Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000718 in 139,280 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency: Genomes: 𝑓 0.0000072 (0 hom., cov: 19)
• Consequence: CTNS NM_004937.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.596

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 0 ACMG points.

• PM1: In a domain PQ-loop 1 (size 66) in uniprot entity CTNS_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004937.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05843699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNS	NM_004937.3	c.487G>C	p.Val163Leu	missense_variant	Exon 8 of 12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.487G>C	p.Val163Leu	missense_variant	Exon 8 of 12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes AF: 0.00000718 AC: 1 AN: 139280 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000758

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000718 AC: 1 AN: 139280 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 67056

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000758

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	7.9
DANN	Benign	0.64
DEOGEN2	Uncertain	0.57	D;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.59	N;N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.4	N;N;.;.
REVEL	Uncertain	0.37
Sift	Benign	1.0	T;T;.;.
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.0010	B;B;.;.
Vest4		0.32
MutPred		0.44		Loss of catalytic residue at V163 (P = 0.0179);Loss of catalytic residue at V163 (P = 0.0179);.;.;
MVP		0.63
MPC		0.16
ClinPred		0.057	T
GERP RS		1.4
Varity_R		0.090
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: rs200818208; hg19: chr17-3559806;