chr2-98389666-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001298.3(CNGA3):c.458C>T(p.Thr153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,696 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T153T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0082 ( 3 hom., cov: 32)

Exomes 𝑓: 0.011 ( 98 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.694

Publications

18 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: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070102513).

BP6

Variant 2-98389666-C-T is Benign according to our data. Variant chr2-98389666-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00824 (1255/152274) while in subpopulation NFE AF = 0.0131 (892/68006). AF 95% confidence interval is 0.0124. There are 3 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGA3	NM_001298.3 link	c.458C>T	p.Thr153Met	missense_variant	Exon 6 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.458C>T	p.Thr153Met	missense_variant	Exon 6 of 8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 link	c.404C>T	p.Thr135Met	missense_variant	Exon 5 of 7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000393503.2 link	n.463C>T		non_coding_transcript_exon_variant	Exon 2 of 2	4
CNGA3	ENST00000409937.1 link	n.611C>T		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.00825

AC:

1255

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00848

AC:

2133

AN:

251484

AF XY:

0.00870

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00783

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00822

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.0109

AC:

15967

AN:

1461422

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

7774

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33470

American (AMR)

AF:

0.00847

AC:

379

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00441

AC:

380

AN:

86236

European-Finnish (FIN)

AF:

0.00900

AC:

481

AN:

53420

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.0126

AC:

13968

AN:

1111786

Other (OTH)

AF:

0.0106

AC:

642

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

826

1652

2478

3304

4130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.00824

AC:

1255

AN:

152274

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

602

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

41562

American (AMR)

AF:

0.00935

AC:

143

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00311

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

892

AN:

68006

Other (OTH)

AF:

0.0147

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00773

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0119

AC:

102

ExAC

AF:

0.00856

AC:

1039

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CNGA3: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 27, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Achromatopsia 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.10

T;.;T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.97

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.34

T;T;.;T

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

0.34

N;.;N;.

PhyloP100

-0.69

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.039

D;T;D;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.19

B;.;B;.

Vest4

0.24

MVP

0.90

MPC

0.12

ClinPred

0.015

GERP RS

-0.19

Varity_R

0.027

gMVP

0.26

Mutation Taster

=100/0

polymorphism

(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