NM_004937.3:c.226-793C>T

Variant names:

• chr17-3654205-C-T
• rs437287
• NM_004937.3:c.226-793C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004937.3(CTNS):​c.226-793C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,120 control chromosomes in the GnomAD database, including 4,823 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4823 hom., cov: 33)
• Consequence: CTNS NM_004937.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 0 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: Myriad Women’s Health
• nephropathic cystinosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P
• juvenile nephropathic cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• ocular cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• nephropathic infantile cystinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105371493 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• 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 rank	MANE	Protein	UniProt
CTNS	NM_004937.3	c.226-793C>T		intron_variant	Intron 5 of 11	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.226-793C>T		intron_variant	Intron 5 of 11	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34791 AN: 152002 Hom.: 4826 Cov.: 33

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.229 AC: 34792 AN: 152120 Hom.: 4823 Cov.: 33 AF XY: 0.232 AC XY: 17288 AN XY: 74366

African (AFR) AF: 0.0853 AC: 3541 AN: 41508

American (AMR) AF: 0.290 AC: 4431 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1135 AN: 3468

East Asian (EAS) AF: 0.507 AC: 2620 AN: 5164

South Asian (SAS) AF: 0.351 AC: 1693 AN: 4818

European-Finnish (FIN) AF: 0.216 AC: 2285 AN: 10586

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18219 AN: 67974

Other (OTH) AF: 0.239 AC: 504 AN: 2110

Alfa AF: 0.241 Hom.: 600

Bravo AF: 0.228

Asia WGS AF: 0.387 AC: 1344 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.75
PhyloP100		0.060
Mutation Taster		=100/0	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: rs437287; hg19: chr17-3557499;