rs1189928623
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_019098.5(CNGB3):āc.806T>Cā(p.Leu269Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,134 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 Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L269L) has been classified as Likely benign.
Frequency
Consequence
NM_019098.5 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 |
---|---|---|---|---|---|---|---|
CNGB3 | NM_019098.5 | c.806T>C | p.Leu269Pro | missense_variant | 6/18 | ENST00000320005.6 | |
CNGB3 | XM_011517138.3 | c.392T>C | p.Leu131Pro | missense_variant | 4/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGB3 | ENST00000320005.6 | c.806T>C | p.Leu269Pro | missense_variant | 6/18 | 1 | NM_019098.5 | P1 | |
CNGB3 | ENST00000681746.1 | c.806T>C | p.Leu269Pro | missense_variant, NMD_transcript_variant | 6/19 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461134Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726900
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Achromatopsia 3 Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Mar 27, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CNGB3 related disorder (ClinVar ID: VCV000427673, PMID:28795510). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.751, 3CNET: 0.879, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28795510, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | 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. 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 CNGB3 protein function. ClinVar contains an entry for this variant (Variation ID: 427673). This missense change has been observed in individual(s) with achromatopsia (PMID: 28795510). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 269 of the CNGB3 protein (p.Leu269Pro). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at