rs104893615

Positions:

chr2-98396839-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_001298.3(CNGA3):c.1669G>A(p.Gly557Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 9.60

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a binding_site (size 123) in uniprot entity CNGA3_HUMAN there are 83 pathogenic changes around while only 1 benign (99%) in NM_001298.3

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-98396839-G-A is Pathogenic according to our data. Variant chr2-98396839-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396839-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-98396839-G-A is described in Lovd as [Pathogenic]. Variant chr2-98396839-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.1669G>A	p.Gly557Arg	missense_variant	8/8	ENST00000272602.7	NP_001289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGA3	ENST00000272602.7 linkuse as main transcript	c.1669G>A	p.Gly557Arg	missense_variant	8/8	1	NM_001298.3	ENSP00000272602	A1	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.1615G>A	p.Gly539Arg	missense_variant	7/7	1		ENSP00000410070	P4	Q16281-2
CNGA3	ENST00000409937.1 linkuse as main transcript	n.1822G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251330

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000112

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2023	Published functional studies demonstrate a damaging effect with alteration of cGMP sensitivity, reduced calcium influx, and decreased cell surface expression compared to wild type (PMID: 18521937); 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: 11536077, 32531858, 9662398, 25616768, 17693388, 18521937, 31456290, 31980526) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 557 of the CNGA3 protein (p.Gly557Arg). This variant is present in population databases (rs104893615, gnomAD 0.3%). This missense change has been observed in individual(s) with achromatopsia (PMID: 17265047, 18521937, 25616768; Invitae). 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: 9476). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CNGA3 function (PMID: 17693388, 18521937). For these reasons, this variant has been classified as Pathogenic. -

Achromatopsia 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

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.1669G>A (p.G557R) alteration is located in exon 8 (coding exon 7) of the CNGA3 gene. This alteration results from a G to A substitution at nucleotide position 1669, causing the glycine (G) at amino acid position 557 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (40/282722) total alleles studied. The highest observed frequency was 0.27% (28/10360) of Ashkenazi Jewish alleles. This alteration is one of the most common founder mutations in the Israeli population (Sharon, 2020). It has been reported in association with achromatopsia and other cone photoreceptor disorders in homozygotes and in heterozygotes with an additional CNGA3 alteration (Kohl, 1998; Wissinger, 2001; Wiszniewski, 2007; Reuter, 2008; Zelinger 2015; Matet, 2018). This amino acid position is highly 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. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 16, 2019

- -

not specified

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 30, 2013

The Gly557Arg variant in CNGA3 has been identified in 1 compound heterozygous individual with achromatopsia (Kohl 1998). Functional studies indicate this variant may alter protein function (Reuter 2008), though the assay is not clinically validated. In summary, although these data favor pathogenicity of the Gly557Arg variant, additional studies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;H;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.5

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.84

MutPred

0.78

.;.;.;Gain of MoRF binding (P = 0.0268);

MVP

0.99

MPC

0.56

ClinPred

0.94

GERP RS

5.4

Varity_R

0.90

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over