chr2-98396398-C-T

Position:

chr2-98396398-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001298.3(CNGA3):c.1228C>T(p.Arg410Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,802 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.50

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 14 ACMG points.

PM1

In a topological_domain Extracellular (size 81) in uniprot entity CNGA3_HUMAN there are 41 pathogenic changes around while only 1 benign (98%) in NM_001298.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 2-98396398-C-T is Pathogenic according to our data. Variant chr2-98396398-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396398-C-T is described in Lovd as [Pathogenic]. Variant chr2-98396398-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.1228C>T	p.Arg410Trp	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.1228C>T	p.Arg410Trp	missense_variant	8/8	1	NM_001298.3	ENSP00000272602	A1	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.1174C>T	p.Arg392Trp	missense_variant	7/7	1		ENSP00000410070	P4	Q16281-2
CNGA3	ENST00000409937.1 linkuse as main transcript	n.1381C>T		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250286

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000656

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 25, 2018	The CNGA3 c.1228C>T (p.Arg410Trp) variant was reported in six individuals with achromatopsia, including one individual who carries the variant in a homozygous state and five individuals, including a sibling pair, who carry the variant in a compound heterozygous state (Kohl et al. 1998; Wissinger et al. 2001; Nishiguchi et al. 2005; Genead et al. 2011; Liang et al. 2015). The variant was also identified in a homozygous state in an individual with cone dystrophy (Dockery et al. 2017). The p.Arg410Trp variant was absent from 190 control individuals (Kohl et al. 1998; Nishiguchi et al. 2005) and is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. When transfected in HEK-293 cells, the p.Arg410Trp variant showed no cGMP channel activity, in contrast to the wild type protein, which showed maximum activity at the same vector concentration, and preliminary studies suggested that the channel function was not rescued when the p.Arg410Trp variant was co-expressed with wild type (Muraki-Oda et al. 2007). Tanaka et al. (2015) demonstrated that the canine orthologous variant, p.Arg424Trp, results in complete loss of channel activity and cone function in vivo, and structural modeling and molecular dynamics simulations suggested the variant disrupted a salt bridge formation. Based on the collective evidence, the p.Arg410Trp variant is classified as pathogenic for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2021	Published functional studies showed no cGMP-activated current by patch-clamp recording technique, suggesting R410W may cause a loss of function of CNG channels (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: 9662398, 17693388, 30682209, 30337596, 31589614, 29099798, 25637600, 21778272, 26407004, 15712225, 11536077, 12187427, 12876837, 27040408) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the CNGA3 protein (p.Arg410Trp). This variant is present in population databases (rs137852608, gnomAD 0.009%). This missense change has been observed in individuals with achromatopsia or cone dystrophy (PMID: 9662398, 11536077, 25637600, 29099798, 30337596). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg411Trp. ClinVar contains an entry for this variant (Variation ID: 9479). 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. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;D;.

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.94

D;D;.;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.;H;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.3

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.80

MutPred

0.68

.;.;.;Loss of disorder (P = 0.0069);

MVP

1.0

MPC

0.50

ClinPred

0.95

GERP RS

1.7

Varity_R

0.85

gMVP

0.83

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