chr17-3656506-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP3BS1_Supporting
The NM_004937.3(CTNS):c.481G>A(p.Asp161Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00003 in 1,598,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000029 ( 0 hom., cov: 19)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
CTNS
NM_004937.3 missense
NM_004937.3 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 6.60
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a domain PQ-loop 1 (size 66) in uniprot entity CTNS_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004937.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.838
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000301 (44/1460902) while in subpopulation EAS AF= 0.000882 (35/39670). AF 95% confidence interval is 0.000652. There are 0 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CTNS | NM_004937.3 | c.481G>A | p.Asp161Asn | missense_variant | 8/12 | ENST00000046640.9 | NP_004928.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CTNS | ENST00000046640.9 | c.481G>A | p.Asp161Asn | missense_variant | 8/12 | 1 | NM_004937.3 | ENSP00000046640 | P1 | |
| CTNS-AS1 | ENST00000575741.1 | n.532+350C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes 0.0000292 AC: 4AN: 137168Hom.: 0 Cov.: 19
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GnomAD3 exomes AF: 0.0000402 AC: 10AN: 248790Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134796
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1460902Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 726682
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GnomAD4 genome 0.0000292 AC: 4AN: 137168Hom.: 0 Cov.: 19 AF XY: 0.0000152 AC XY: 1AN XY: 65822
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ocular cystinosis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 18, 2021 | - - |
Nephropathic cystinosis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.
Sift4G
Pathogenic
D;D;.;D;D
Polyphen
D;D;.;.;.
Vest4
MVP
MPC
0.67
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at