rs267606701
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001159773.2(CANT1):c.898C>T(p.Arg300Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,597,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R300H) has been classified as Pathogenic.
Frequency
Consequence
NM_001159773.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CANT1 | NM_001159773.2 | c.898C>T | p.Arg300Cys | missense_variant | 5/5 | ENST00000392446.10 | |
CANT1 | NM_001159772.2 | c.898C>T | p.Arg300Cys | missense_variant | 6/6 | ||
CANT1 | NM_138793.4 | c.898C>T | p.Arg300Cys | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CANT1 | ENST00000392446.10 | c.898C>T | p.Arg300Cys | missense_variant | 5/5 | 1 | NM_001159773.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000175 AC: 4AN: 229118Hom.: 0 AF XY: 0.0000318 AC XY: 4AN XY: 125794
GnomAD4 exome AF: 0.0000138 AC: 20AN: 1445590Hom.: 0 Cov.: 31 AF XY: 0.0000209 AC XY: 15AN XY: 718438
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
Desbuquois dysplasia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | This missense change has been observed in individuals with Desbuquois dysplasia (PMID: 19853239). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CANT1 protein function. ClinVar contains an entry for this variant (Variation ID: 279). This variant is present in population databases (rs267606701, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 300 of the CANT1 protein (p.Arg300Cys). Experimental studies have shown that this missense change affects CANT1 function (PMID: 19853239, 21037275). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg300 amino acid residue in CANT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19853239, 22539336). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at