NM_004937.3:c.462T>C

Variant names:

• chr17-3656487-T-C
• rs77453839
• NM_004937.3:c.462T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004937.3(CTNS):​c.462T>C​(p.Ser154Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,587,498 control chromosomes in the GnomAD database, including 1,608 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (702 hom., cov: 17)
  • Exomes 𝑓: 0.0078 (906 hom.)
• Consequence: CTNS NM_004937.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006894
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.32
• Publications: 5 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-AS1 (HGNC:56090): (CTNS antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 17-3656487-T-C is Benign according to our data. Variant chr17-3656487-T-C is described in ClinVar as Benign. ClinVar VariationId is 257153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 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.462T>C	p.Ser154Ser	splice_region synonymous	Exon 8 of 12	NP_004928.2	O60931-1
	CTNS	NM_001031681.3		c.462T>C	p.Ser154Ser	splice_region synonymous	Exon 8 of 13	NP_001026851.2	O60931-2
	CTNS	NM_001374492.1		c.462T>C	p.Ser154Ser	splice_region synonymous	Exon 8 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.462T>C	p.Ser154Ser	splice_region synonymous	Exon 8 of 12	ENSP00000046640.4	O60931-1
	CTNS	ENST00000381870.8	TSL:1	c.462T>C	p.Ser154Ser	splice_region synonymous	Exon 8 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000488623.6	TSL:3	c.-292T>C		splice_region	Exon 7 of 11	ENSP00000501016.1	A0A669KAZ5

Frequencies

GnomAD3 genomes AF: 0.0496 AC: 6421 AN: 129490 Hom.: 694 Cov.: 17

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00150

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.000710

Gnomad OTH AF: 0.0327

GnomAD2 exomes AF: 0.0186 AC: 4545 AN: 244426 AF XY: 0.0156

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.00958

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000772

Gnomad FIN exome AF: 0.0000482

Gnomad NFE exome AF: 0.000707

Gnomad OTH exome AF: 0.00786

GnomAD4 exome AF: 0.00783 AC: 11420 AN: 1457914 Hom.: 906 Cov.: 32 AF XY: 0.00765 AC XY: 5543 AN XY: 725042

African (AFR) AF: 0.222 AC: 7394 AN: 33292

American (AMR) AF: 0.0106 AC: 468 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00121 AC: 48 AN: 39522

South Asian (SAS) AF: 0.0233 AC: 2000 AN: 85700

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53026

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5764

European-Non Finnish (NFE) AF: 0.000511 AC: 567 AN: 1110072

Other (OTH) AF: 0.0146 AC: 880 AN: 60228

GnomAD4 genome AF: 0.0498 AC: 6455 AN: 129584 Hom.: 702 Cov.: 17 AF XY: 0.0496 AC XY: 3078 AN XY: 62074

African (AFR) AF: 0.194 AC: 6036 AN: 31068

American (AMR) AF: 0.0197 AC: 238 AN: 12062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3288

East Asian (EAS) AF: 0.00151 AC: 7 AN: 4648

South Asian (SAS) AF: 0.0193 AC: 71 AN: 3686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8628

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.000710 AC: 45 AN: 63354

Other (OTH) AF: 0.0323 AC: 56 AN: 1734

Alfa AF: 0.0255 Hom.: 664

Bravo AF: 0.0702

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cystinosis (1)
-	-	1	Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis (1)
-	-	1	Nephropathic cystinosis (1)
-	-	1	not specified (1)
-	-	1	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.5
DANN	Benign	0.50
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=60/40	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.010		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: rs77453839; hg19: chr17-3559781;