rs104893621

chr2-98396476-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001298.3(CNGA3):c.1306C>T(p.Arg436Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,912 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R436Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: CNGA3 NM_001298.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 1.57

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001298.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-98396477-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2581658.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 2-98396476-C-T is Pathogenic according to our data. Variant chr2-98396476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396476-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-98396476-C-T is described in Lovd as [Pathogenic]. Variant chr2-98396476-C-T is described in Lovd as [Pathogenic]. Variant chr2-98396476-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.1306C>T	p.Arg436Trp	missense_variant	8/8	ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7	c.1306C>T	p.Arg436Trp	missense_variant	8/8	1	NM_001298.3	A1
CNGA3	ENST00000436404.6	c.1252C>T	p.Arg418Trp	missense_variant	7/7	1		P4
CNGA3	ENST00000409937.1	n.1459C>T		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000957 AC: 24 AN: 250684 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135586

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000698 AC: 102 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 2 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R436W in CNGA3 (NM_001298.3) has been previously reported in multiple affected individuals (Li S et al,Huang L et al). Functional studies suggest a damaging effect (Muraki-Oda S et al). In silico tools are damaging and the residue is poorly conserved across species. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2022	Variant summary: CNGA3 c.1306C>T (p.Arg436Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250684 control chromosomes. c.1306C>T has been reported in the literature in multiple individuals affected with Achromatopsia and has been shown to segregate in families (eg. Saqib_2015, Wissinger_2001, etc). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown the variant to have absent cGMP-activated current upon patch-clamp recordings, suggesting that this mutation causes a loss of function of the channels (Muraki-Oda_2007). Additionally, a mouse model demonstrated the variant to result in a loss of activity and impaired cellular trafficking, as a result of changes to the secondary structure (Matveev_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	not provided	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	-	- -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 436 of the CNGA3 protein (p.Arg436Trp). This variant is present in population databases (rs104893621, gnomAD 0.04%). This missense change has been observed in individuals with retinal dystrophy (PMID: 11536077, 25943428, 26992781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9482). 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: 17693388). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2022	Published functional studies demonstrate a damaging effect with loss of activity and impaired cellular trafficking, as a result of changes to the secondary structure (Muraki-Oda et al., 2007; Matveev et al., 2010); This variant is associated with the following publications: (PMID: 16961972, 32531858, 26992781, 20088482, 11536077, 25943428, 25616768, 21778272, 15712225, 14757870, 17693388, 30804581, 30609409, 30682209, 24903488, 30418171, 31456290, 33083013, 34426522) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CNGA3: PM3:Very Strong, PM1, PM2, PS3:Supporting -

Achromatopsia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2017	The p.Arg436Trp (NM001298.2 c.1306C>T) variant in CNGA3 has been reported in at least 2 homozygous and 10 compound heterozygous individuals with clinical diagno sis of achromatopsia or cone-rod dystrophy (Li 2014, Wissinger 2001, Johnson 200 4, Goto-Omoto 2006, Saqib 2015, Huang 2016, Nishiguchi 2005, Zelinger 2015, and Genead 2011), and segregated in 3 affected homozygous family members in one fami ly (Saqib 2015). This variant has also been identified in 0.036% (6/16,458) of S outh Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs104893621). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessi ve carrier frequency. In summary, this variant meets criteria to be classified a s pathogenic for CNGA3-related achromatopsia/ cone-rod dystrophy in an autosomal recessive manner based upon its biallelic occurrence in affected individuals an d low frequency in control populations. -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 20, 2018	- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.59	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.86
MVP		1.0
MPC		0.52
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.75
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: rs104893621; hg19: chr2-99012939; COSMIC: COSV55625945;