rs756806434
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001297.5(CNGB1):c.3142_3143insGTGG(p.Ala1048GlyfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000095 ( 0 hom. )
Consequence
CNGB1
NM_001297.5 frameshift
NM_001297.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
CNGB1 (HGNC:2151): (cyclic nucleotide gated channel subunit beta 1) In humans, the rod photoreceptor cGMP-gated cation channel helps regulate ion flow into the rod photoreceptor outer segment in response to light-induced alteration of the levels of intracellular cGMP. This channel consists of two subunits, alpha and beta, with the protein encoded by this gene representing the beta subunit. Defects in this gene are a cause of cause of retinitis pigmentosa type 45. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 16-57897496-G-GCCAC is Pathogenic according to our data. Variant chr16-57897496-G-GCCAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGB1 | NM_001297.5 | c.3142_3143insGTGG | p.Ala1048GlyfsTer13 | frameshift_variant | 31/33 | ENST00000251102.13 | |
CNGB1 | NM_001286130.2 | c.3124_3125insGTGG | p.Ala1042GlyfsTer13 | frameshift_variant | 31/33 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGB1 | ENST00000251102.13 | c.3142_3143insGTGG | p.Ala1048GlyfsTer13 | frameshift_variant | 31/33 | 1 | NM_001297.5 | P4 | |
CNGB1 | ENST00000564448.5 | c.3124_3125insGTGG | p.Ala1042GlyfsTer13 | frameshift_variant | 31/33 | 1 | A2 | ||
CNGB1 | ENST00000565942.1 | c.188_189insGTGG | p.Ala64GlyfsTer13 | frameshift_variant | 3/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249502Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135388
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GnomAD4 exome AF: 0.0000951 AC: 139AN: 1461836Hom.: 0 Cov.: 33 AF XY: 0.000102 AC XY: 74AN XY: 727226
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74292
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Ala1048GlyfsTer13 variant in CNGB1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change creates a premature translational stop signal (p.Ala1048Glyfs*13) in the CNGB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGB1 are known to be pathogenic (PMID: 15557452, 24043777). This variant is present in population databases (rs756806434, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 28056120). ClinVar contains an entry for this variant (Variation ID: 437975). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 17, 2018 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at