rs147415641

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1PP2PP3BP4_StrongBS1_SupportingBS2

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:3U: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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM1

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

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, cone-rod dystrophy, Leber congenital amaurosis 9, CNGA3-related retinopathy, achromatopsia 2.

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

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

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000841 (128/152240) while in subpopulation SAS AF = 0.0127 (61/4822). AF 95% confidence interval is 0.0101. There are 2 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGA3	NM_001298.3 link	c.682G>A	p.Glu228Lys	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.682G>A	p.Glu228Lys	missense_variant	Exon 8 of 8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 link	c.628G>A	p.Glu210Lys	missense_variant	Exon 7 of 7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000409937.1 link	n.835G>A		non_coding_transcript_exon_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.00137

AC:

345

AN:

251304

AF XY:

0.00180

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 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

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.0000671

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0000756

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0101

AC:

871

AN:

86204

Gnomad4 FIN exome

AF:

0.0000374

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.0000252

AC:

AN:

1111990

Gnomad4 Remaining exome

AF:

0.000878

AC:

AN:

60396

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000841

AC:

128

AN:

152240

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00157

AC:

0.00156559

AN:

0.00156559

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.0127

AC:

0.0126504

AN:

0.0126504

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294031

AN:

0.0000294031

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

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:

0.000285

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:3Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Achromatopsia

Pathogenic:2

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

- -

Achromatopsia 2

Uncertain:2

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

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. -

Oct 13, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1Benign:1

Jun 27, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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;.

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

Mutation Taster

=24/76

disease causing (ClinVar)

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