chr17-3656590-C-T

Variant names:

• chr17-3656590-C-T
• rs111256750
• NM_004937.3:c.561+4C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001031681.3(CTNS):​c.561+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,611,828 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: CTNS NM_001031681.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002242
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: -1.82
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-3656590-C-T is Benign according to our data. Variant chr17-3656590-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257156.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000348 (508/1461426) while in subpopulation AFR AF = 0.000358 (12/33478). AF 95% confidence interval is 0.000291. There are 2 homozygotes in GnomAdExome4. There are 217 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	NM_004937.3	MANE Select	c.561+4C>T		splice_region intron	N/A	NP_004928.2
	CTNS	NM_001031681.3		c.561+4C>T		splice_region intron	N/A	NP_001026851.2
	CTNS	NM_001374492.1		c.561+4C>T		splice_region intron	N/A	NP_001361421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.561+4C>T		splice_region intron	N/A	ENSP00000046640.4
	CTNS	ENST00000381870.8	TSL:1	c.561+4C>T		splice_region intron	N/A	ENSP00000371294.3
	CTNS	ENST00000673965.1		c.561+4C>T		splice_region intron	N/A	ENSP00000500995.1

Frequencies

GnomAD3 genomes AF: 0.000379 AC: 57 AN: 150286 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00211

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000340

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 250906 AF XY: 0.000317

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461426 Hom.: 2 Cov.: 33 AF XY: 0.000298 AC XY: 217 AN XY: 727006

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00193 AC: 103 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000318 AC: 354 AN: 1111734

Other (OTH) AF: 0.000447 AC: 27 AN: 60388

GnomAD4 genome AF: 0.000379 AC: 57 AN: 150402 Hom.: 0 Cov.: 28 AF XY: 0.000395 AC XY: 29 AN XY: 73426

African (AFR) AF: 0.000270 AC: 11 AN: 40788

American (AMR) AF: 0.0000665 AC: 1 AN: 15028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00211 AC: 22 AN: 10434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000340 AC: 23 AN: 67704

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000261

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.37
DANN	Benign	0.77
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.012
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: rs111256750; hg19: chr17-3559884; COSMIC: COSV50439899; COSMIC: COSV50439899;