2-98346189-A-G

Position:

• chr2-98346189-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000436404(CNGA3):​c.-383A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 395,798 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (1 hom.)
• Consequence: CNGA3 ENST00000436404 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.12

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-98346189-A-G is Benign according to our data. Variant chr2-98346189-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337646.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.98346189A>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGA3	ENST00000436404	c.-383A>G		5_prime_UTR_variant	1/7	1		ENSP00000410070.2
ENSG00000222000	ENST00000454230.1	n.191+9626T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.00269 AC: 655 AN: 243522 Hom.: 1 Cov.: 0 AF XY: 0.00282 AC XY: 348 AN XY: 123472

Gnomad4 AFR exome AF: 0.000281

Gnomad4 AMR exome AF: 0.000272

Gnomad4 ASJ exome AF: 0.000218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00733

Gnomad4 FIN exome AF: 0.00831

Gnomad4 NFE exome AF: 0.00265

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152276 Hom.: 4 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74466

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CNGA3: BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Achromatopsia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs143449407; hg19: chr2-98962652;