rs141386891
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong
The NM_001298.3(CNGA3):c.1279C>T(p.Arg427Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000512 in 1,613,950 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427L) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00052 ( 3 hom. )
Consequence
CNGA3
NM_001298.3 missense
NM_001298.3 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 4.62
Genes affected
CNGA3 (HGNC:2150): (cyclic nucleotide gated channel subunit alpha 3) This gene encodes a member of the cyclic nucleotide-gated cation channel protein family which is required for normal vision and olfactory signal transduction. Mutations in this gene are associated with achromatopsia (rod monochromacy) and color blindness. Two alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_001298.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-98396450-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 989367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
Variant 2-98396449-C-T is Pathogenic according to our data. Variant chr2-98396449-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 497256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396449-C-T is described in Lovd as [Likely_benign]. Variant chr2-98396449-C-T is described in Lovd as [Pathogenic]. Variant chr2-98396449-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-98396449-C-T is described in Lovd as [Pathogenic]. Variant chr2-98396449-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA3 | NM_001298.3 | c.1279C>T | p.Arg427Cys | missense_variant | 8/8 | ENST00000272602.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGA3 | ENST00000272602.7 | c.1279C>T | p.Arg427Cys | missense_variant | 8/8 | 1 | NM_001298.3 | A1 | |
CNGA3 | ENST00000436404.6 | c.1225C>T | p.Arg409Cys | missense_variant | 7/7 | 1 | P4 | ||
CNGA3 | ENST00000409937.1 | n.1432C>T | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000395 AC: 60AN: 152084Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000395 AC: 99AN: 250474Hom.: 1 AF XY: 0.000517 AC XY: 70AN XY: 135484
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GnomAD4 exome AF: 0.000525 AC: 767AN: 1461748Hom.: 3 Cov.: 31 AF XY: 0.000546 AC XY: 397AN XY: 727154
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GnomAD4 genome AF: 0.000394 AC: 60AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74404
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 427 of the CNGA3 protein (p.Arg427Cys). This variant is present in population databases (rs141386891, gnomAD 0.2%). This missense change has been observed in individual(s) with achromatopsia or cone dystrophy (PMID: 11536077, 18445228, 23972307, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 497256). 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 CNGA3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CNGA3 function (PMID: 18445228). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2021 | Published functional studies of this variant demonstrates that cGMP maximum currents of mutant channels were reduced, and the chemical chaperone glycerol significantly enhanced surface expression of mutant channels and macroscopic currents, which may indicate impaired folding and trafficking of the mutant channel protein (Koeppen et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31290651, 30418171, 30653986, 28559085, 30682209, 28341476, 23362848, 24148654, 18445228, 23972307, 24269407, 17652762, 11536077, 15712225, 17693388, 16961972, 19874885, 3039450) - |
Achromatopsia 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with achromatopsia 2 (MIM#216900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been described within sibling pairs (PMID: 30682209). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (108 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg427Leu)) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and observed in compound heterozygous individuals with achromatopsia and retinal dystrophy (ClinVar, LOVD, PMID: 30653986). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 17, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5. - |
Achromatopsia Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Mar 20, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2018 | The p.Arg427Cys variant in CNGA3 has been reported in 9 compound heterozygous in dividuals with clinical diagnosis of achromatopsia or cone-rod dystrophy (Wissin ger 2001, Koeppen 2008, Fahim 2013, Taylor 2017), and segregated in 2 affected f amily members (Koeppen 2008, Fahim 2013). This variant has also been identified in 0.15% (47/30754) of South Asian chromosomes, including 1 homozygote, by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs1 41386891). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In vi tro functional studies provide some evidence that the p.Arg427Cys variant may im pact protein function, resulting in a decreased channel density in the cell memb rane (Koeppen 2008, Muraki-Oda 2007). In summary, this variant is pathogenic for achromatopsia in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_ VeryStrong; PS3_Moderate; PP3; PP1. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 31, 2023 | - - |
Abnormality of the eye Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 02, 2018 | - - |
Macular dystrophy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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