Genetic Variant CTNS:p.Asn323Asn (chr17-3659974-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_004937.3(CTNS):c.969C>T(p.Asn323Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,611,624 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00081 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

CTNS
NM_004937.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0002420

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.895

Publications

14 publications found

Variant links:

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

CTNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 17-3659974-C-T is Benign according to our data. Variant chr17-3659974-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284194.

BP7

Synonymous conserved (PhyloP=-0.895 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000807 (123/152348) while in subpopulation AFR AF = 0.00272 (113/41594). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNS	NM_004937.3	MANE Select	c.969C>T	p.Asn323Asn	splice_region synonymous	Exon 11 of 12	NP_004928.2	O60931-1
CTNS	NM_001031681.3		c.969C>T	p.Asn323Asn	splice_region synonymous	Exon 11 of 13	NP_001026851.2	O60931-2
CTNS	NM_001374492.1		c.969C>T	p.Asn323Asn	splice_region synonymous	Exon 11 of 13	NP_001361421.1	O60931-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNS	ENST00000046640.9	TSL:1 MANE Select	c.969C>T	p.Asn323Asn	splice_region synonymous	Exon 11 of 12	ENSP00000046640.4	O60931-1
CTNS	ENST00000381870.8	TSL:1	c.969C>T	p.Asn323Asn	splice_region synonymous	Exon 11 of 13	ENSP00000371294.3	O60931-2
CTNS	ENST00000673965.1		c.969C>T	p.Asn323Asn	splice_region synonymous	Exon 11 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000239

AC:

AN:

250840

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000822

AC:

120

AN:

1459276

Hom.:

Cov.:

AF XY:

0.0000634

AC XY:

AN XY:

726012

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33422

American (AMR)

AF:

0.000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110304

Other (OTH)

AF:

0.000149

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000807

AC:

123

AN:

152348

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00272

AC:

113

AN:

41594

American (AMR)

AF:

0.000392

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.000907

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystinosis (1)

Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.4

(source)

DANN

Benign

0.89

PhyloP100

-0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.022

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over