rs777367316

Positions:

• chr17-3647455-A-G
• chr17-3647455-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004937.3(CTNS):​c.73A>G​(p.Ser25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTNS NM_004937.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372

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]

LOC105371493 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07173872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.73A>G	p.Ser25Gly	missense_variant	4/12	ENST00000046640.9	NP_004928.2
LOC105371493	XR_007065579.1	n.1935-2280T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.73A>G	p.Ser25Gly	missense_variant	4/12	1	NM_004937.3	ENSP00000046640	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	6.4
DANN	Benign	0.80
DEOGEN2	Benign	0.26	T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.45	T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.072	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.7	L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;D;D;.
REVEL	Benign	0.23
Sift	Benign	0.22	T;T;T;T;.
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.13
MutPred		0.24		Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);
MVP		0.67
MPC		0.15
ClinPred		0.041	T
GERP RS		-6.3
Varity_R		0.045
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs777367316; hg19: chr17-3550749;