chr17-3660669-C-A

Variant names:

• chr17-3660669-C-A
• rs2873624
• ENST00000381870.8:c.1138C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001031681.3(CTNS):​c.1138C>A​(p.Pro380Thr) 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. 16/20 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. P380A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CTNS NM_001031681.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.224
• Publications: 0 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: ClinGen, Myriad Women’s Health
• nephropathic cystinosis

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058736116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031681.3. 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.*300C>A		3_prime_UTR	Exon 12 of 12	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.1138C>A	p.Pro380Thr	missense	Exon 13 of 13	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.1138C>A	p.Pro380Thr	missense	Exon 13 of 13	NP_001361421.1	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000381870.8	TSL:1	c.1138C>A	p.Pro380Thr	missense	Exon 13 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.*300C>A		3_prime_UTR	Exon 12 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000574776.6	TSL:4	c.697C>A	p.Pro233Thr	missense	Exon 10 of 10	ENSP00000461118.2	I3L4A9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.2
DANN	Benign	0.65
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.059	T
MetaSVM	Uncertain	-0.10	T
PhyloP100		0.22
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.14
Sift	Benign	0.44	T
Sift4G	Benign	0.34	T
Polyphen		0.013	B
Vest4		0.068
MVP		0.26
MPC		0.19
ClinPred		0.059	T
GERP RS		1.4
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2873624; hg19: chr17-3563963; COSMIC: COSV107218284; COSMIC: COSV107218284;