rs146195955

Positions:

chr2-98396137-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The ENST00000272602.7(CNGA3):c.967G>C(p.Ala323Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A323D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CNGA3
ENST00000272602.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 5.27

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000272602.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 2-98396137-G-C is Pathogenic according to our data. Variant chr2-98396137-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 284032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98396137-G-C is described in Lovd as [Likely_pathogenic]. Variant chr2-98396137-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.967G>C	p.Ala323Pro	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.967G>C	p.Ala323Pro	missense_variant	8/8	1	NM_001298.3	ENSP00000272602	A1	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.913G>C	p.Ala305Pro	missense_variant	7/7	1		ENSP00000410070	P4	Q16281-2
CNGA3	ENST00000409937.1 linkuse as main transcript	n.1120G>C		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251488

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000302

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000694

Hom.:

Bravo

AF:

0.000317

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PM3 (moderate),PM2,PP3,PM5,PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2023	Variant summary: CNGA3 c.967G>C (p.Ala323Pro) results in a non-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 7.6e-05 in 251488 control chromosomes. c.967G>C has been reported in the literature in multiple individuals affected with Achromatopsia and other CNGA3-related diseases including rod monochromacy and macular degenerations, either being seen with second pathogenic variants or being homozygous (example: Hitti-malin_2022, Mejecase_2020, Sun_2020, Solaki_2022). These data indicate that the variant is very likely to be associated with Achromatopsia 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36259723, 32783370, 32913385, 35332618). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=4; Likely pathogenic, n=1; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2024	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: 36259723, 36460718, 31725702, 30289319, 32581362, 32783370, 28041643, 37372476, 38219857) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 323 of the CNGA3 protein (p.Ala323Pro). This variant is present in population databases (rs146195955, gnomAD 0.09%). This missense change has been observed in individual(s) with cone rod dystrophy and achromatopsia (PMID: 28041643, 30289319; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284032). 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%. This variant disrupts the p.Ala323 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 26493561), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2018	- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 31, 2019

- -

Cone dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;.;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.048

D;D;D;D

Sift4G

Benign

0.096

T;T;T;T

Polyphen

0.99

D;.;D;.

Vest4

0.85

MVP

1.0

MPC

0.20

ClinPred

0.37

GERP RS

5.0

Varity_R

0.98

gMVP

0.99

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