17-3655055-G-T

Variant names:

• chr17-3655055-G-T
• rs121908124
• NM_004937.3:c.283G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004937.3(CTNS):​c.283G>T​(p.Gly95*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G95G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNS NM_004937.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.17
• Publications: 3 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 Gene-Disease associations (from GenCC):

• cystinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• nephropathic cystinosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P
• juvenile nephropathic cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• ocular cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• nephropathic infantile cystinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105371493 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3655055-G-T is Pathogenic according to our data. Variant chr17-3655055-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4441.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	NM_004937.3	MANE Select	c.283G>T	p.Gly95*	stop_gained	Exon 6 of 12	NP_004928.2
	CTNS	NM_001374493.1		c.-159G>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 11	NP_001361422.1
	CTNS	NM_001374494.1		c.-159G>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 11	NP_001361423.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.283G>T	p.Gly95*	stop_gained	Exon 6 of 12	ENSP00000046640.4
	CTNS	ENST00000381870.8	TSL:1	c.283G>T	p.Gly95*	stop_gained	Exon 6 of 13	ENSP00000371294.3
	CTNS	ENST00000673669.1		c.-159G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	ENSP00000501123.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nephropathic cystinosis Pathogenic:1

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		8.2
Vest4		0.97
GERP RS		5.0
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 46

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

Other links and lift over

dbSNP: rs121908124; hg19: chr17-3558349;