chr17-3636842-A-G

Variant names:

• chr17-3636842-A-G
• rs116000219
• NM_004937.3:c.-230+11A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004937.3(CTNS):​c.-230+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 152,404 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (247 hom., cov: 33)
  • Exomes 𝑓: 0.018 (0 hom.)
• Consequence: CTNS NM_004937.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.624
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 17-3636842-A-G is Benign according to our data. Variant chr17-3636842-A-G is described in ClinVar as Benign. ClinVar VariationId is 322825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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.-230+11A>G		intron	N/A	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.-230+134A>G		intron	N/A	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.-230+11A>G		intron	N/A	NP_001361421.1	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.-230+11A>G		intron	N/A	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.-230+134A>G		intron	N/A	ENSP00000371294.3	O60931-2
	CTNS	ENST00000941478.1		c.-494A>G		5_prime_UTR	Exon 1 of 11	ENSP00000611537.1

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4773 AN: 152172 Hom.: 245 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0175 AC: 2 AN: 114 Hom.: 0 Cov.: 0 AF XY: 0.0217 AC XY: 2 AN XY: 92

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.0270 AC: 2 AN: 74

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 36

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0315 AC: 4800 AN: 152290 Hom.: 247 Cov.: 33 AF XY: 0.0315 AC XY: 2347 AN XY: 74474

African (AFR) AF: 0.105 AC: 4347 AN: 41544

American (AMR) AF: 0.0118 AC: 181 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68006

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0248 Hom.: 13

Bravo AF: 0.0347

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	8.6
DANN	Benign	0.73
PhyloP100		-0.62
PromoterAI		-0.058	Neutral
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: rs116000219; hg19: chr17-3540136;