rs1800528

Variant names:

• chr17-3656529-G-A
• rs1800528
• NM_004937.3:c.504G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001031681.3(CTNS):​c.504G>A​(p.Thr168Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,603,876 control chromosomes in the GnomAD database, including 28,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2048 hom., cov: 22)
  • Exomes 𝑓: 0.19 (26763 hom.)
• Consequence: CTNS NM_001031681.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.823
• Publications: 18 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-AS1 (HGNC:56090): (CTNS antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-3656529-G-A is Benign according to our data. Variant chr17-3656529-G-A is described in ClinVar as Benign. ClinVar VariationId is 257154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.823 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 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.504G>A	p.Thr168Thr	synonymous	Exon 8 of 12	NP_004928.2
	CTNS	NM_001031681.3		c.504G>A	p.Thr168Thr	synonymous	Exon 8 of 13	NP_001026851.2
	CTNS	NM_001374492.1		c.504G>A	p.Thr168Thr	synonymous	Exon 8 of 13	NP_001361421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.504G>A	p.Thr168Thr	synonymous	Exon 8 of 12	ENSP00000046640.4
	CTNS	ENST00000381870.8	TSL:1	c.504G>A	p.Thr168Thr	synonymous	Exon 8 of 13	ENSP00000371294.3
	CTNS	ENST00000673965.1		c.504G>A	p.Thr168Thr	synonymous	Exon 8 of 12	ENSP00000500995.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 21548 AN: 142748 Hom.: 2043 Cov.: 22

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0590

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.184 AC: 45835 AN: 249472 AF XY: 0.183

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.202

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.188 AC: 274004 AN: 1461020 Hom.: 26763 Cov.: 35 AF XY: 0.187 AC XY: 135920 AN XY: 726802

African (AFR) AF: 0.0357 AC: 1196 AN: 33466

American (AMR) AF: 0.228 AC: 10163 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3415 AN: 26134

East Asian (EAS) AF: 0.177 AC: 7003 AN: 39660

South Asian (SAS) AF: 0.167 AC: 14408 AN: 86200

European-Finnish (FIN) AF: 0.236 AC: 12537 AN: 53202

Middle Eastern (MID) AF: 0.180 AC: 1040 AN: 5768

European-Non Finnish (NFE) AF: 0.192 AC: 213199 AN: 1111622

Other (OTH) AF: 0.183 AC: 11043 AN: 60372

GnomAD4 genome AF: 0.151 AC: 21565 AN: 142856 Hom.: 2048 Cov.: 22 AF XY: 0.153 AC XY: 10529 AN XY: 69028

African (AFR) AF: 0.0425 AC: 1617 AN: 38018

American (AMR) AF: 0.194 AC: 2696 AN: 13910

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 423 AN: 3388

East Asian (EAS) AF: 0.201 AC: 967 AN: 4816

South Asian (SAS) AF: 0.168 AC: 715 AN: 4262

European-Finnish (FIN) AF: 0.232 AC: 2190 AN: 9448

Middle Eastern (MID) AF: 0.171 AC: 49 AN: 286

European-Non Finnish (NFE) AF: 0.190 AC: 12540 AN: 65900

Other (OTH) AF: 0.163 AC: 315 AN: 1930

Alfa AF: 0.165 Hom.: 1222

Bravo AF: 0.145

Asia WGS AF: 0.196 AC: 681 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Nephropathic cystinosis (2)
-	-	2	Ocular cystinosis (2)
-	-	1	Cystinosis (1)
-	-	1	Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.2
DANN	Benign	0.87
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1800528; hg19: chr17-3559823; COSMIC: COSV50440774; COSMIC: COSV50440774;