rs886063161
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_019098.5(CNGB3):c.886_896delACTTCTACAAAinsT(p.Thr296TyrfsTer9) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_019098.5 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CNGB3 | NM_019098.5 | c.886_896delACTTCTACAAAinsT | p.Thr296TyrfsTer9 | frameshift_variant, missense_variant | Exon 7 of 18 | ENST00000320005.6 | NP_061971.3 | |
| CNGB3 | XM_011517138.3 | c.472_482delACTTCTACAAAinsT | p.Thr158TyrfsTer9 | frameshift_variant, missense_variant | Exon 5 of 16 | XP_011515440.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CNGB3 | ENST00000320005.6 | c.886_896delACTTCTACAAAinsT | p.Thr296TyrfsTer9 | frameshift_variant, missense_variant | Exon 7 of 18 | 1 | NM_019098.5 | ENSP00000316605.5 | ||
| CNGB3 | ENST00000681546.1 | n.706_716delACTTCTACAAAinsT | non_coding_transcript_exon_variant | Exon 2 of 13 | ||||||
| CNGB3 | ENST00000681746.1 | n.886_896delACTTCTACAAAinsT | non_coding_transcript_exon_variant | Exon 7 of 19 | ENSP00000505959.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Achromatopsia 3 Pathogenic:2
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CNGB3-related disorder Pathogenic:2
The CNGB3 c.886_896delinsT variant is predicted to result in a frameshift and premature protein termination (p.Thr296Tyrfs*9). This variant has been reported in the compound heterozygous state in individuals with achromatopsia and/or cone dystrophy (Kohl et al. 2005. PubMed ID: 15657609; Thiadens et al. 2010. PubMed ID: 20079539; Weisschuh et al 2020. PubMed ID: 32531858; Table S2, Del Pozo-Valero et al. 2022. PubMed ID: 35119454). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Frameshift variants in CNGB3 are an established mechanism of disease. Given the evidence, we interpret this variant as pathogenic. -
The CNGB3 c.886_896delACTTCTACAAAinsT (p.Thr296TyrfsTer9) variant is a frameshift variant that is predicted to result in premature termination of the protein. The variant has been reported in a total of seven individuals with achromatopsia, including six who were compound heterozygous for the variant and one who was heterozygous without a second identified variant (Kohl et al. 2005). The variant has not been reported in association with Stargardt disease, though Thiadens et al. (2010) reported two unrelated individuals with autosomal recessive progressive cone dystrophy who were both compound heterozygous for the p.Thr296TyrfsTer9 variant and a second null variant. An unaffected parent and an unaffected child of one of the individuals were both heterozygous. The p.Thr296TyrfsTer9 variant was absent from 100 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Thr296TyrfsTer9 variant is classified as pathogenic for CNGB3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided Pathogenic:2
The c.886_896del11insT variant in the CNGB3 gene has been reported previously in association with achromatopsia and progressive cone dystrophy (Thiadens et al., 2010; Kohl et al., 2005). This variant causes a frameshift starting with codon Threonine 296, changes this amino acid to a Tyrosine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Thr296TyrfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.886_896del11insT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.886_896del11insT as a pathogenic variant. -
This sequence change creates a premature translational stop signal (p.Thr296Tyrfs*9) in the CNGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 28795510). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 15657609, 20079539, 23362848). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. -
Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at