2-98395999-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_001298.3(CNGA3):c.829C>T(p.Arg277Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,100 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. R277H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.58

Publications

22 publications found

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 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

CNGA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001298.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-98396000-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 800983.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, 0.962

PP5

Variant 2-98395999-C-T is Pathogenic according to our data. Variant chr2-98395999-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9481.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 link	c.829C>T	p.Arg277Cys	missense_variant	Exon 8 of 8	ENST00000272602.7	NP_001289.1	Q16281-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNGA3	ENST00000272602.7 link	c.829C>T	p.Arg277Cys	missense_variant	Exon 8 of 8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 link	c.775C>T	p.Arg259Cys	missense_variant	Exon 7 of 7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000409937.1 link	n.982C>T		non_coding_transcript_exon_variant	Exon 8 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000955

AC:

AN:

251350

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000975

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Jul 23, 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 cysteine, which is neutral and slightly polar, at codon 277 of the CNGA3 protein (p.Arg277Cys). This variant is present in population databases (rs104893620, gnomAD 0.02%). This missense change has been observed in individuals with achromatopsia and cone dystrophy (PMID: 11536077). ClinVar contains an entry for this variant (Variation ID: 9481). 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: 20238023). This variant disrupts the p.Arg277 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11536077, 17693388, 26992781). 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. -

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 07, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect as R277C impaired channel activity compared to wild type CNGA3 (PMID: 17693388); 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: 20238023, 36833446, 31964843, 34321860, 21912902, 14736794, 14757870, 15712225, 16961972, 18521937, 31589614, 31429209, 32531858, 37734845, 15743887, 21911670, 26992781, 19592100, 24049715, 18445228, 23082193, 30682209, 30653986, 30418171, 31456290, 35119454, 34449556, 11536077, 17693388) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Achromatopsia 2

Pathogenic:4

Oct 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Achromatopsia

Pathogenic:2

Mar 20, 2018

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Optic atrophy

Pathogenic:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration;C0085636:Photophobia;C0234629:Color vision defect

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

H;.;H;.

PhyloP100

3.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.0

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.83

MVP

1.0

MPC

0.60

ClinPred

0.96

GERP RS

5.2

Varity_R

0.89

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over