chr2-98396476-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.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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 1.57

Publications

20 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001298.3

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 VariationId is 2581658.

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, 0.948

PP5

Variant 2-98396476-C-T is Pathogenic according to our data. Variant chr2-98396476-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9482.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.1306C>T	p.Arg436Trp	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.1306C>T	p.Arg436Trp	missense_variant	Exon 8 of 8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 link	c.1252C>T	p.Arg418Trp	missense_variant	Exon 7 of 7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000409937.1 link	n.1459C>T		non_coding_transcript_exon_variant	Exon 8 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000957

AC:

AN:

250684

AF XY:

0.000111

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.000313

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1112012

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.0000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41514

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00125

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000101

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 2

Pathogenic:7

Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 26, 2022

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.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. -

not provided

Pathogenic:5

Oct 23, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CNGA3: PM3:Very Strong, PM1, PM2, PS3:Supporting -

Aug 12, 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 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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Achromatopsia

Pathogenic:3

Mar 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 20, 2018

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinal dystrophy

Pathogenic:2

May 13, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2017

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

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;D;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.59

LIST_S2

Pathogenic

0.99

D;D;.;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;H;.

PhyloP100

1.6

PrimateAI

Uncertain

0.68

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

GERP RS

4.0

Varity_R

0.75

gMVP

0.87

Mutation Taster

=2/98

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