NM_004937.3:c.-21_-20delAG

Variant names:

• chr17-3637312-CAG-C
• rs550436044
• NM_004937.3:c.-21_-20delAG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_004937.3(CTNS):​c.-21_-20delAG variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 152,222 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTNS NM_004937.3 splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0950
• 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: ClinGen, Myriad Women’s Health
• nephropathic cystinosis

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000388 (59/152222) while in subpopulation SAS AF = 0.00892 (43/4818). AF 95% confidence interval is 0.00681. There are 1 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004937.3. 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.-21_-20delAG		splice_region	Exon 2 of 12	NP_004928.2	O60931-1
	CTNS	NM_004937.3	MANE Select	c.-21_-20delAG		5_prime_UTR	Exon 2 of 12	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.-21_-20delAG		splice_region	Exon 2 of 13	NP_001026851.2	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.-32_-31delAG		5_prime_UTR	Exon 2 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.-32_-31delAG		5_prime_UTR	Exon 2 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.-32_-31delAG		5_prime_UTR	Exon 2 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152104 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 36 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 24

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 30

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152222 Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74426

African (AFR) AF: 0.0000722 AC: 3 AN: 41544

American (AMR) AF: 0.000654 AC: 10 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000253

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cystinosis (1)
-	1	-	Nephropathic cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.095
Mutation Taster		=298/2	polymorphism

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: rs550436044; hg19: chr17-3540606;