rs199584830
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001379270.1(CNGA1):c.1528C>T(p.Arg510*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,692 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 (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )
Consequence
CNGA1
NM_001379270.1 stop_gained
NM_001379270.1 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.79
Genes affected
CNGA1 (HGNC:2148): (cyclic nucleotide gated channel subunit alpha 1) The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene. [provided by RefSeq, Oct 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-47936954-G-A is Pathogenic according to our data. Variant chr4-47936954-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-47936954-G-A is described in Lovd as [Pathogenic]. Variant chr4-47936954-G-A is described in Lovd as [Pathogenic]. Variant chr4-47936954-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CNGA1 | NM_001379270.1 | c.1528C>T | p.Arg510* | stop_gained | 11/11 | ENST00000514170.7 | NP_001366199.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CNGA1 | ENST00000514170.7 | c.1528C>T | p.Arg510* | stop_gained | 11/11 | 5 | NM_001379270.1 | ENSP00000426862.3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 151992Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000522 AC: 13AN: 249112Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135136
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GnomAD4 exome AF: 0.0000848 AC: 124AN: 1461700Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54AN XY: 727110
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 151992Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74214
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinal dystrophy Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 10, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2018 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2023 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 177 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 32581362, 26306921, 30337596, 33576794, 31456290, 26582918, 36819107, 32037395, 33749171, 24077912) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2023 | This sequence change creates a premature translational stop signal (p.Arg514*) in the CNGA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the CNGA1 protein. This variant is present in population databases (rs199584830, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 30337596). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236443). This variant disrupts the C-terminus of the CNGA1 protein. Other variant(s) that disrupt this region (p.Arg560*, p.Arg629*, p.Arg658Aspfs*2) have been observed in individuals with CNGA1-related conditions (PMID: 7479749, 24154662, 25611614). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa Pathogenic:2
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Retinitis pigmentosa 49 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CNGA1 c.1747C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. - |
Retinitis pigmentosa;C3151059:Retinitis pigmentosa 49 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 01, 2021 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
Vest4
GERP RS
Splicing
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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