rs6727412

Positions:

• chr2-98370047-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001298.3(CNGA3):​c.72T>C​(p.Asp24=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,068 control chromosomes in the GnomAD database, including 22,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1617 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21264 hom.)
• Consequence: CNGA3 NM_001298.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.36

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-98370047-T-C is Benign according to our data. Variant chr2-98370047-T-C is described in ClinVar as [Benign]. Clinvar id is 257964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98370047-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3	c.72T>C	p.Asp24=	synonymous_variant	2/8	ENST00000272602.7	NP_001289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGA3	ENST00000272602.7	c.72T>C	p.Asp24=	synonymous_variant	2/8	1	NM_001298.3	ENSP00000272602	A1
CNGA3	ENST00000436404.6	c.72T>C	p.Asp24=	synonymous_variant	2/7	1		ENSP00000410070	P4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20632 AN: 151904 Hom.: 1617 Cov.: 32

Gnomad AFR AF: 0.0990

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.00618

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0972

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.133 AC: 33270 AN: 250736 Hom.: 2564 AF XY: 0.136 AC XY: 18377 AN XY: 135498

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.00625

Gnomad SAS exome AF: 0.0878

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.164 AC: 239850 AN: 1461046 Hom.: 21264 Cov.: 33 AF XY: 0.163 AC XY: 118387 AN XY: 726824

Gnomad4 AFR exome AF: 0.0955

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.00433

Gnomad4 SAS exome AF: 0.0907

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.136 AC: 20650 AN: 152022 Hom.: 1617 Cov.: 32 AF XY: 0.130 AC XY: 9670 AN XY: 74306

Gnomad4 AFR AF: 0.0990

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.00620

Gnomad4 SAS AF: 0.0821

Gnomad4 FIN AF: 0.0972

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.159

Alfa AF: 0.169 Hom.: 3085

Bravo AF: 0.139

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.186

EpiControl AF: 0.190

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Achromatopsia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Apr 15, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.53
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6727412; hg19: chr2-98986510; COSMIC: COSV55624351;