rs104893617

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001298.3(CNGA3):c.1641C>A(p.Phe547Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. 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. F547C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 1 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.0300

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 18 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-98396810-T-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 2-98396811-C-A is Pathogenic according to our data. Variant chr2-98396811-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396811-C-A is described in Lovd as [Pathogenic]. Variant chr2-98396811-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-98396811-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-98396811-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 link	c.1641C>A	p.Phe547Leu	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 link	c.1641C>A	p.Phe547Leu	missense_variant	8/8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 link	c.1587C>A	p.Phe529Leu	missense_variant	7/7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000409937.1 link	n.1794C>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152140

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:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251308

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000930

AC:

136

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000737

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000112

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000582

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 2

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2023	Variant summary: CNGA3 c.1641C>A (p.Phe547Leu) results in a non-conservative amino acid change located in the cyclic nucleotide-binding domain (IPR000595) of 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 0.00015 in 251308 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1641C>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Achromatopsia 2 (e.g., Sun_2020). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 32913385). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 12, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PP3,PP4. This variant was detected in homozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.F547L in CNGA3 (NM_001298.3) has been reported previously in homozygous as well as compound heterozygous state in affected indviduals (Fahim AT et al; Georgiou M et al).It is known to affect protein function (Muraki-Oda S et al). It has been submitted to ClinVar as Pathogenic/Likely Pathogenic. It is present in 45 alleles in heterozygous state in the gnomad database (0.1%) as well as it has been observed in homozygous state in one individual. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	CNGA3: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 547 of the CNGA3 protein (p.Phe547Leu). This variant is present in population databases (rs104893617, gnomAD 0.07%). This missense change has been observed in individual(s) with achromatopsia (PMID: 9662398, 11536077, 14757870, 23972307, 30682209). 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: 9478). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Published functional studies demonstrate loss of electrophysiological activity in the mutant channel compared to wild type (Matveev et al., 2010; Muraki-Oda et al., 2007); 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: 16961972, 31429209, 32531858, 23972307, 20088482, 9662398, 17693388, 18521937, 25168900, 27040408, 19592100, 11536077, 14757870, 24148654, 16319819, 30682209, 30653986, 31456290, 33562422, 31589614, 34426522, 34449556) -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 23, 2019	- -

Monochromacy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 21, 2014

- -

Achromatopsia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;D;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

1.0

D;D;.;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;M;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.9

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.96

MutPred

0.94

.;.;.;Loss of sheet (P = 0.1398);

MVP

0.97

MPC

0.55

ClinPred

0.81

GERP RS

1.9

Varity_R

0.89

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

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