17-3655669-C-A

Position:

• chr17-3655669-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004937.3(CTNS):​c.461+317C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 402,266 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (523 hom., cov: 31)
  • Exomes 𝑓: 0.023 (142 hom.)
• Consequence: CTNS NM_004937.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.202

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-3655669-C-A is Benign according to our data. Variant chr17-3655669-C-A is described in ClinVar as [Benign]. Clinvar id is 1227016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.461+317C>A		intron_variant		ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.461+317C>A		intron_variant		1	NM_004937.3	ENSP00000046640	P1
CTNS-AS1	ENST00000575741.1	n.826G>T		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.0566 AC: 8586 AN: 151826 Hom.: 520 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0529

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0445

GnomAD4 exome AF: 0.0233 AC: 5835 AN: 250322 Hom.: 142 Cov.: 0 AF XY: 0.0230 AC XY: 3103 AN XY: 134730

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.0000817

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0566 AC: 8599 AN: 151944 Hom.: 523 Cov.: 31 AF XY: 0.0561 AC XY: 4165 AN XY: 74290

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.0331

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0441

Alfa AF: 0.0413 Hom.: 40

Bravo AF: 0.0596

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.58

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: rs9907296; hg19: chr17-3558963;