rs753625117
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001298.3(CNGA3):āc.955T>Cā(p.Cys319Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (ā ā ).
Frequency
Consequence
NM_001298.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA3 | NM_001298.3 | c.955T>C | p.Cys319Arg | missense_variant | 8/8 | ENST00000272602.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGA3 | ENST00000272602.7 | c.955T>C | p.Cys319Arg | missense_variant | 8/8 | 1 | NM_001298.3 | A1 | |
CNGA3 | ENST00000436404.6 | c.901T>C | p.Cys301Arg | missense_variant | 7/7 | 1 | P4 | ||
CNGA3 | ENST00000409937.1 | n.1108T>C | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251480Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135908
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461894Hom.: 1 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CNGA3 function (PMID: 25052312). 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 CNGA3 protein function. ClinVar contains an entry for this variant (Variation ID: 191120). This missense change has been observed in individuals with inherited retinal disease (PMID: 25052312, 26355662). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs753625117, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 319 of the CNGA3 protein (p.Cys319Arg). - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | - | - - |
Achromatopsia 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.C319R in CNGA3 (NM_001298.3) has been observed previously in homozygous state in affected individuals (Shaikh RS et al, Patel N et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.C319R variant is observed in 4/30,616 (0.0131%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.C319R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The cysteine residue at codon 319 of CNGA3 is conserved in all mammalian species. The nucleotide c.955 in CNGA3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at