rs104893619

Positions:

chr2-98396755-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001298.3(CNGA3):c.1585G>A(p.Val529Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,110 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 (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

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:

CNGA3 (HGNC:):

CNGA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a strand (size 3) in uniprot entity CNGA3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001298.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 2-98396755-G-A is Pathogenic according to our data. Variant chr2-98396755-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396755-G-A is described in Lovd as [Pathogenic]. Variant chr2-98396755-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-98396755-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.1585G>A	p.Val529Met	missense_variant	8/8	ENST00000272602.7	NP_001289.1	Q16281-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CNGA3	ENST00000272602.7 linkuse as main transcript	c.1585G>A	p.Val529Met	missense_variant	8/8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.1531G>A	p.Val511Met	missense_variant	7/7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000409937.1 linkuse as main transcript	n.1738G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152228

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251096

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2024	Published functional studies suggest a damaging effect, however additional studies are needed to validate the functional effect of this variant in vivo (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: 31429209, 31964843, 33749171, 26992781, 31456290, 31589614, 34426522, 9662398, 15712225, 20549516, 17693388, 38219857) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 529 of the CNGA3 protein (p.Val529Met). This variant is present in population databases (rs104893619, gnomAD 0.03%). This missense change has been observed in individual(s) with achromatopsia or inherited retinal dystrophy (PMID: 9662398, 15712225, 20549516, 24903488). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9480). 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). For these reasons, this variant has been classified as Pathogenic. -

Achromatopsia 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 05, 2020	The CNGA3 c.1585G>A (p.Val529Met) variant is a missense variant that has been reported in at least four studies, in which it was found in at least 14 unrelated individuals with achromatopsia, including nine in a homozygous state and five in a compound heterozygous state (Kohl et al. 1998; Wissinger et al. 2001; Nishiguchi et al. 2005; Zelinger et al. 2010). The p.Val529Met variant was absent from 190 controls but is reported at a frequency of 0.000301 in the East Asian population from the Genome Aggregation Database. In patch-clamp studies of HEK293 cells transfected with p.Val529Met variant cDNA, no cGMP-activated current was observed (Muraki-Oda et al. 2007). Based on the collective evidence and application of the ACMG criteria, the p.Val529Met variant is classified as pathogenic for achromatopsia. -

Achromatopsia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

CNGA3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The CNGA3 c.1585G>A variant is predicted to result in the amino acid substitution p.Val529Met. This variant has been reported in the homozygous and compound heterozygous states in several individuals with cone rod dystrophy and achromatopsia (see for examples: Kohl et al. 1998. PubMed ID: 9662398; Huang et al. 2016. PubMed ID: 26992781: Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;H;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.8

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

0.92

MVP

0.98

MPC

0.51

ClinPred

0.68

GERP RS

5.1

Varity_R

0.86

gMVP

0.83

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