rs141386891

chr2-98396449-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM5 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1
• 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]

ACMG classification

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: 60 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000395 AC: 99 AN: 250474 Hom.: 1 AF XY: 0.000517 AC XY: 70 AN XY: 135484

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000525 AC: 767 AN: 1461748 Hom.: 3 Cov.: 31 AF XY: 0.000546 AC XY: 397 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74404

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000411 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2016	- -
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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
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. -

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	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 31, 2023	- -
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	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 20, 2018	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.9	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.81
MVP		0.99
MPC		0.60
ClinPred		0.43	T
GERP RS		4.8
Varity_R		0.84
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141386891; hg19: chr2-99012912;