2-98370042-C-T

Position:

chr2-98370042-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001298.3(CNGA3):c.67C>T(p.Arg23Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,826 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CNGA3
NM_001298.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.361

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.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 502 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-98370042-C-T is Pathogenic according to our data. Variant chr2-98370042-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 337652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98370042-C-T is described in Lovd as [Pathogenic]. Variant chr2-98370042-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-98370042-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.67C>T	p.Arg23Ter	stop_gained	2/8	ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7 linkuse as main transcript	c.67C>T	p.Arg23Ter	stop_gained	2/8	1	NM_001298.3	A1	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.67C>T	p.Arg23Ter	stop_gained	2/7	1		P4	Q16281-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251056

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000236

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 2

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The CNGA3 c.67C>T (p.Arg23Ter) stop-gained variant was reported in at least five individuals with achromatopsia or another cone dystrophy, including two homozygotes and three compound heterozygotes, and in two unaffected heterozygous parents of individuals (Johnson et al. 2004; Koeppen et al. 2008; Sundaram et al. 2014; Aboshiha et al. 2014; Zelinger et al. 2015; Huang et al. 2016). The variant was absent from six control individuals and from 100 control chromosomes. The variant is reported at a frequency of 0.00012 in the East Asian population of the Exome Aggregation Consortium, but this is based on only one allele in a region of good sequence coverage so it is presumed to be rare. Based on the evidence and due to the potential impact of stop-gained variants, the p.Arg23Ter variant is classified as pathogenic for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Achromatopsia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2023

This sequence change creates a premature translational stop signal (p.Arg23*) in the CNGA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGA3 are known to be pathogenic (PMID: 14757870, 24903488, 25637600). This variant is present in population databases (rs777509481, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with CNGA3-related conditions (PMID: 14757870, 30682209). ClinVar contains an entry for this variant (Variation ID: 337652). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.075

MutationTaster

Benign

1.0

A;A;A

Vest4

0.62

GERP RS

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: -16

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