Genetic Variant NM_004937.3:c.108C>T (chr17-3647490-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004937.3(CTNS):c.108C>T(p.Asn36Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00801 in 1,614,108 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 103 hom. )

Consequence

CTNS
NM_004937.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.03

Publications

1 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:

LOC105371493 (HGNC:):

LOC105371493 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 17-3647490-C-T is Benign according to our data. Variant chr17-3647490-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 322835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0063 (959/152298) while in subpopulation NFE AF = 0.0083 (565/68032). AF 95% confidence interval is 0.00774. There are 13 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

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.108C>T	p.Asn36Asn	synonymous	Exon 4 of 12	NP_004928.2	O60931-1
CTNS	NM_001374493.1		c.-249C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 11	NP_001361422.1	A0A669KB82
CTNS	NM_001374494.1		c.-334C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001361423.1	A0A669KB82

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNS	ENST00000046640.9	TSL:1 MANE Select	c.108C>T	p.Asn36Asn	synonymous	Exon 4 of 12	ENSP00000046640.4	O60931-1
CTNS	ENST00000381870.8	TSL:1	c.108C>T	p.Asn36Asn	synonymous	Exon 4 of 13	ENSP00000371294.3	O60931-2
CTNS	ENST00000673669.1		c.-249C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000501123.1	A0A669KB82

Frequencies

GnomAD3 genomes

AF:

0.00630

AC:

959

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0228

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00830

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00706

AC:

1775

AN:

251418

AF XY:

0.00697

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00819

AC:

11969

AN:

1461810

Hom.:

103

Cov.:

AF XY:

0.00787

AC XY:

5724

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.000783

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00325

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0215

AC:

1149

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00929

AC:

10330

AN:

1111978

Other (OTH)

AF:

0.00550

AC:

332

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

642

1284

1925

2567

3209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.00630

AC:

959

AN:

152298

Hom.:

Cov.:

AF XY:

0.00682

AC XY:

508

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41564

American (AMR)

AF:

0.00144

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0228

AC:

242

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00830

AC:

565

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00728

Hom.:

Bravo

AF:

0.00473

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00693

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cystinosis (1)

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

Nephropathic cystinosis (1)

not specified (1)

Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.3

(source)

DANN

Benign

0.56

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism

(source)

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

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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