rs138958917

chr2-98391964-C-Gchr2-98391964-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

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: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.886

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-98391965-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 865874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 [Likely_pathogenic]. Clinvar id is 812278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-98391964-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA3	NM_001298.3	c.667C>G	p.Arg223Gly	missense_variant	7/8	ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7	c.667C>G	p.Arg223Gly	missense_variant	7/8	1	NM_001298.3	A1
CNGA3	ENST00000436404.6	c.613C>G	p.Arg205Gly	missense_variant	6/7	1		P4
CNGA3	ENST00000409937.1	n.820C>G		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251150 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135756

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000938 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Achromatopsia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2021

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. -

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;.
MutationTaster	Benign	1.0	D;D;D;D
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

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: rs138958917; hg19: chr2-99008427;