rs138958917

Variant names:

• chr2-98391964-C-G
• rs138958917
• NM_001298.3:c.667C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-98391964-C-G
• chr2-98391964-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001298.3(CNGA3):​c.667C>G​(p.Arg223Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,402 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CNGA3 NM_001298.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.886
• Publications: 17 publications found

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]

CNGA3 Gene-Disease associations (from GenCC):

• achromatopsia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia
• CNGA3-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• achromatopsia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-98391965-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 865874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 105 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Trascript score misZ: 0.49806 (below the threshold of 3.09). GenCC associations: The gene is linked to achromatopsia 2, CNGA3-related retinopathy, cone-rod dystrophy, achromatopsia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 2-98391964-C-G is Pathogenic according to our data. Variant chr2-98391964-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 812278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGA3	NM_001298.3	c.667C>G	p.Arg223Gly	missense_variant	Exon 7 of 8	ENST00000272602.7	NP_001289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGA3	ENST00000272602.7	c.667C>G	p.Arg223Gly	missense_variant	Exon 7 of 8	1	NM_001298.3	ENSP00000272602.2
CNGA3	ENST00000436404.6	c.613C>G	p.Arg205Gly	missense_variant	Exon 6 of 7	1		ENSP00000410070.2
CNGA3	ENST00000409937.1	n.820C>G		non_coding_transcript_exon_variant	Exon 7 of 8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251150 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461402 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111858

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000828 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 2 Pathogenic:1

Apr 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CNGA3 c.667C>G (p.Arg223Gly) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of 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 3.6e-05 in 251150 control chromosomes. c.667C>G has been observed in a compound heterozygous individual affected with Achromatopsia 2 (Wiszniewski_2007). It has also been reported in two Jewish individuals with inherited retinal diseases without clarification of the second allele variants (Sharon_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Solaki_2023). The following publications have been ascertained in the context of this evaluation (PMID: 31456290, 37689994, 17265047). ClinVar contains an entry for this variant (Variation ID: 812278). Based on the evidence outlined above, the variant was classified as pathogenic. -

Achromatopsia Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Aug 28, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667C>G (p.R223G) alteration is located in exon 7 (coding exon 6) of the CNGA3 gene. This alteration results from a C to G substitution at nucleotide position 667, causing the arginine (R) at amino acid position 223 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (9/251150) total alleles studied. The highest observed frequency was 0.09% (9/10080) of Ashkenazi Jewish alleles. This alteration has been reported in a patient with achromatopsia in combination with a second CNGA3 alteration (Wiszniewski, 2007). Two alterations affecting the same amino acid, p.R223W and p.R223Q, have also been reported in association with achromatopsia (Wissinger, 2001; Fahim, 2013; Greenberg, 2014; Li, 2014). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 223 of the CNGA3 protein (p.Arg223Gly). This variant is present in population databases (rs138958917, gnomAD 0.08%). This missense change has been observed in individual(s) with achromatopsia (PMID: 17265047, 31456290; internal data). 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: 812278). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CNGA3 protein function. This variant disrupts the p.Arg223 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11536077, 23972307). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H;.
PhyloP100		0.89
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.97
MutPred		0.81		.;.;.;Loss of methylation at R227 (P = 0.0298);
MVP		1.0
MPC		0.58
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.83
gMVP		0.87
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs138958917; hg19: chr2-99008427;