rs147415641

Positions:

chr2-98395852-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_001298.3(CNGA3):c.682G>A(p.Glu228Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000724 in 1,614,058 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 12 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3B:2

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 31) in uniprot entity CNGA3_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_001298.3

BP4

Computational evidence support a benign effect (MetaRNN=0.030779868).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.682G>A	p.Glu228Lys	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.682G>A	p.Glu228Lys	missense_variant	8/8	1	NM_001298.3	ENSP00000272602	A1	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.628G>A	p.Glu210Lys	missense_variant	7/7	1		ENSP00000410070	P4	Q16281-2
CNGA3	ENST00000409937.1 linkuse as main transcript	n.835G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00137

AC:

345

AN:

251304

Hom.:

AF XY:

0.00180

AC XY:

244

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000711

AC:

1040

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000976

AC XY:

710

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000841

AC:

128

AN:

152240

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00157

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0127

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000638

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00155

AC:

188

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Achromatopsia

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 20, 2018	- -

Achromatopsia 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CNGA3 c.682G>A (p.Glu228Lys) variant was identified in a homozygous state in two siblings with achromatopsia (Reuter et al. 2008). A third individual was found to carry the p.Glu228Lys variant in a compound heterozygous state with a second missense variant along with a homozygous missense variant in the CNGB3 gene (Thiadens et al. 2010). The p.Glu228Lys variant was absent from 100 controls and is reported at a frequency of 0.01005 in the South Asian population of the Exome Aggregation Consortium. Expression of wild type and p.Glu228Lys forms of the A3 channel in HEK293 cells revealed that p.Glu228Lys channels were localized intracellularly instead of at the cell membrane and showed decreased channel density compared to wild type. Based on the evidence, the p.Glu228Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous p.Glu228Lys variant in CNGA3 has been identified in 2 siblings from 1 family with incomplete achromatopsia and in the heterozygous state in an individual with a different eye phenotype and other missense variants (PMID: 18521937, 20079539), and has been identified in >1% of South Asian chromosomes and a homozygote by ExAC (http://gnomad.broadinstitute.org/). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Glu228Lys variant may slightly impact protein function (PMID: 18521937). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2023	Variant summary: CNGA3 c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251304 control chromosomes in the gnomAD database, including 2 homozygotes. c.682G>A was found in homozygous state in two siblings with incomplete Achromatopsia (Reuter_ 2008), and in individuals affected with cone dystrophy (Thiadens _2010 and Hitti-malin_CNGA3_HM_2022). In at-least, one of these individuals affected with cone dystrophy authors reported a homozygous variant in CNGB3 (Thiadens _2010). These report(s) do not provide unequivocal conclusions about association of the variant with Achromatopsia 2. At least one publication reports experimental evidence evaluating an impact on protein function. However, it does not provide strong conclusions about the variant association with the disease (Reuter_ 2008). The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 30418171, 36259723, 27535533, 18521937, 26036949, 31456290, 32913385, 20079539). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2), pathogenic/likely pathogenic (n=2) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D

MetaRNN

Benign

0.031

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.96

D;.;D;.

Vest4

0.89

MVP

0.99

MPC

0.42

ClinPred

0.057

GERP RS

5.3

Varity_R

0.90

gMVP

0.78

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