rs2873624

Positions:

• chr17-3660669-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/17 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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.*300C>G		3_prime_UTR_variant	12/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.*300C>G		3_prime_UTR_variant	12/12	1	NM_004937.3	ENSP00000046640.4

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

GnomAD3 exomes AF: 0.260 AC: 65181 AN: 251162 Hom.: 9669 AF XY: 0.258 AC XY: 35087 AN XY: 135836

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 SAS exome AF: 0.227

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

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.473

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.253

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

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.207

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

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro380Ala in exon 13 of CTNS: This variant is not expected to have clinical si gnificance because it has been identified in 49.67% (4271/8598) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2873624). -

Ocular cystinosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Nephropathic cystinosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2873624; hg19: chr17-3563963; COSMIC: COSV50439911; COSMIC: COSV50439911;