rs35086888

Variant names:

• chr17-3647506-G-A
• rs35086888
• NM_004937.3:c.124G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-3647506-G-A
• chr17-3647506-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004937.3(CTNS):​c.124G>A​(p.Val42Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,614,070 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (79 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (88 hom.)
• Consequence: CTNS NM_004937.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13
• Conservation: PhyloP100: 0.865
• Publications: 13 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

LOC105371493 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021084845).
• BP6: Variant 17-3647506-G-A is Benign according to our data. Variant chr17-3647506-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 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.124G>A	p.Val42Ile	missense	Exon 4 of 12	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.124G>A	p.Val42Ile	missense	Exon 4 of 13	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.124G>A	p.Val42Ile	missense	Exon 4 of 13	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.124G>A	p.Val42Ile	missense	Exon 4 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.124G>A	p.Val42Ile	missense	Exon 4 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.124G>A	p.Val42Ile	missense	Exon 4 of 12	ENSP00000500995.1	O60931-1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2585 AN: 152170 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00444 AC: 1115 AN: 251340 AF XY: 0.00331

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00182 AC: 2662 AN: 1461782 Hom.: 88 Cov.: 31 AF XY: 0.00155 AC XY: 1125 AN XY: 727196

African (AFR) AF: 0.0662 AC: 2215 AN: 33476

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111970

Other (OTH) AF: 0.00351 AC: 212 AN: 60396

GnomAD4 genome AF: 0.0170 AC: 2591 AN: 152288 Hom.: 79 Cov.: 33 AF XY: 0.0164 AC XY: 1224 AN XY: 74460

African (AFR) AF: 0.0597 AC: 2483 AN: 41558

American (AMR) AF: 0.00536 AC: 82 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00602 Hom.: 52

Bravo AF: 0.0194

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0574 AC: 253

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00544 AC: 660

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Cystinosis (2)
-	-	2	Nephropathic cystinosis (2)
-	-	1	CTNS-related disorder (1)
1	-	-	Cystinosis, atypical nephropathic (1)
-	-	1	Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)
-	-	1	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	4.5
DANN	Uncertain	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.93	L
PhyloP100		0.86
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.17
Sift	Benign	0.49	T
Sift4G	Benign	0.69	T
Polyphen		0.0090	B
Vest4		0.13
MVP		0.78
MPC		0.13
ClinPred		0.0054	T
GERP RS		3.0
Varity_R		0.018
gMVP		0.27
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs35086888; hg19: chr17-3550800; COSMIC: COSV99062025;