rs1554614038
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_019098.5(CNGB3):c.682_683insG(p.Ala228GlyfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CNGB3
NM_019098.5 frameshift
NM_019098.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.01
Genes affected
CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-86667094-G-GC is Pathogenic according to our data. Variant chr8-86667094-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 427651.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CNGB3 | NM_019098.5 | c.682_683insG | p.Ala228GlyfsTer3 | frameshift_variant | 6/18 | ENST00000320005.6 | NP_061971.3 | |
CNGB3 | XM_011517138.3 | c.268_269insG | p.Ala90GlyfsTer3 | frameshift_variant | 4/16 | XP_011515440.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CNGB3 | ENST00000320005.6 | c.682_683insG | p.Ala228GlyfsTer3 | frameshift_variant | 6/18 | 1 | NM_019098.5 | ENSP00000316605 | P1 | |
CNGB3 | ENST00000681746.1 | c.682_683insG | p.Ala228GlyfsTer3 | frameshift_variant, NMD_transcript_variant | 6/19 | ENSP00000505959 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461704Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727152
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Achromatopsia 3 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Mar 27, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 427651). This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 15657609, 28795510). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala228Glyfs*3) 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). - |
Computational scores
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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