rs121908129

chr17-3655101-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004937.3(CTNS):c.329G>T(p.Gly110Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G110S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNS NM_004937.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.44

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-3655101-G-T is Pathogenic according to our data. Variant chr17-3655101-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 4457.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNS	NM_004937.3	c.329G>T	p.Gly110Val	missense_variant, splice_region_variant	6/12	ENST00000046640.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNS	ENST00000046640.9	c.329G>T	p.Gly110Val	missense_variant, splice_region_variant	6/12	1	NM_004937.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cystinosis, atypical nephropathic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	26
Dann	Benign	0.93
DEOGEN2	Uncertain	0.42	T;.;.
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.51	N;N;.
REVEL	Uncertain	0.41
Sift	Benign	0.32	T;T;.
Sift4G	Benign	0.53	T;T;T
Polyphen		0.13	B;B;.
Vest4		0.52
MutPred		0.39		Loss of disorder (P = 0.0246);Loss of disorder (P = 0.0246);Loss of disorder (P = 0.0246);
MVP		0.93
MPC		0.22
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.20
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908129; hg19: chr17-3558395;