rs104893612

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001298.3(CNGA3):c.488C>A(p.Pro163Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,488 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CNGA3
NM_001298.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.53

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-98389696-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

PP5

Variant 2-98389696-C-A is Pathogenic according to our data. Variant chr2-98389696-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2331651.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGA3	NM_001298.3 link	c.488C>A	p.Pro163Gln	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.488C>A	p.Pro163Gln	missense_variant	Exon 6 of 8	1	NM_001298.3	ENSP00000272602.2	Q16281-1
CNGA3	ENST00000436404.6 link	c.434C>A	p.Pro145Gln	missense_variant	Exon 5 of 7	1		ENSP00000410070.2	Q16281-2
CNGA3	ENST00000393503.2 link	n.493C>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
CNGA3	ENST00000409937.1 link	n.641C>A		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461488

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 163 of the CNGA3 protein (p.Pro163Gln). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro163 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9662398, 17693388, 23105016). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 2331651). This variant has not been reported in the literature in individuals affected with CNGA3-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Inborn genetic diseases

Uncertain:1

Dec 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488C>A (p.P163Q) alteration is located in exon 6 (coding exon 5) of the CNGA3 gene. This alteration results from a C to A substitution at nucleotide position 488, causing the proline (P) at amino acid position 163 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.;D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;.;T

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;.;M;.

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-6.6

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.012

D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.93

MutPred

0.72

.;.;.;Gain of catalytic residue at P167 (P = 0.0193);

MVP

0.99

MPC

0.46

ClinPred

1.0

GERP RS

4.7

Varity_R

0.46

gMVP

0.85

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over