chr17-3660669-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001031681.3(CTNS):​c.1138C>G​(p.Pro380Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,518 control chromosomes in the GnomAD database, including 53,928 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4011 hom., cov: 34)
  • Exomes 𝑓: 0.25 (49917 hom.)
• Consequence: CTNS NM_001031681.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.224
• Publications: 24 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4540553E-4).
• BP6: Variant 17-3660669-C-G is Benign according to our data. Variant chr17-3660669-C-G is described in ClinVar as Benign. ClinVar VariationId is 257152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

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>G		3_prime_UTR	Exon 12 of 12	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.1138C>G	p.Pro380Ala	missense	Exon 13 of 13	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.1138C>G	p.Pro380Ala	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>G	p.Pro380Ala	missense	Exon 13 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.*300C>G		3_prime_UTR	Exon 12 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000574776.6	TSL:4	c.697C>G	p.Pro233Ala	missense	Exon 10 of 10	ENSP00000461118.2	I3L4A9

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30767 AN: 152164 Hom.: 4015 Cov.: 34

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.260 AC: 65181 AN: 251162 AF XY: 0.258

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.514

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.254 AC: 371558 AN: 1461236 Hom.: 49917 Cov.: 43 AF XY: 0.254 AC XY: 184552 AN XY: 726934

African (AFR) AF: 0.0368 AC: 1232 AN: 33480

American (AMR) AF: 0.310 AC: 13868 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 7196 AN: 26136

East Asian (EAS) AF: 0.473 AC: 18782 AN: 39700

South Asian (SAS) AF: 0.227 AC: 19603 AN: 86258

European-Finnish (FIN) AF: 0.212 AC: 11208 AN: 52786

Middle Eastern (MID) AF: 0.180 AC: 1041 AN: 5768

European-Non Finnish (NFE) AF: 0.255 AC: 283367 AN: 1111998

Other (OTH) AF: 0.253 AC: 15261 AN: 60388

GnomAD4 genome AF: 0.202 AC: 30761 AN: 152282 Hom.: 4011 Cov.: 34 AF XY: 0.203 AC XY: 15137 AN XY: 74460

African (AFR) AF: 0.0473 AC: 1968 AN: 41584

American (AMR) AF: 0.264 AC: 4043 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 970 AN: 3470

East Asian (EAS) AF: 0.507 AC: 2616 AN: 5162

South Asian (SAS) AF: 0.227 AC: 1098 AN: 4830

European-Finnish (FIN) AF: 0.209 AC: 2218 AN: 10614

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17129 AN: 67998

Other (OTH) AF: 0.207 AC: 437 AN: 2116

Alfa AF: 0.236 Hom.: 1462

Bravo AF: 0.202

TwinsUK AF: 0.258 AC: 958

ALSPAC AF: 0.251 AC: 966

ESP6500AA AF: 0.0538 AC: 237

ESP6500EA AF: 0.260 AC: 2240

ExAC AF: 0.251 AC: 30440

Asia WGS AF: 0.308 AC: 1071 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.252

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Nephropathic cystinosis (2)
-	-	2	not specified (2)
-	-	2	Ocular cystinosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.4
DANN	Benign	0.55
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.00015	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.22
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.15
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.028
MPC		0.16
ClinPred		0.00047	T
GERP RS		1.4
gMVP		0.57
Mutation Taster		=98/2	polymorphism (auto)

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: COSV50439911; COSMIC: COSV50439911;