rs139544302

Positions:

• chr2-98377783-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_001298.3(CNGA3):​c.198C>T​(p.Thr66=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,611,346 control chromosomes in the GnomAD database, including 3 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 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: CNGA3 NM_001298.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.294

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-98377783-C-T is Benign according to our data. Variant chr2-98377783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257962.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-0.294 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA3	NM_001298.3	c.198C>T	p.Thr66=	synonymous_variant	3/8	ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7	c.198C>T	p.Thr66=	synonymous_variant	3/8	1	NM_001298.3	A1
CNGA3	ENST00000436404.6	c.198C>T	p.Thr66=	synonymous_variant	3/7	1		P4
CNGA3	ENST00000409937.1	n.186C>T		non_coding_transcript_exon_variant	2/8	2

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00145 AC: 357 AN: 245884 Hom.: 0 AF XY: 0.00131 AC XY: 175 AN XY: 133356

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00209 AC: 3050 AN: 1459048 Hom.: 2 Cov.: 31 AF XY: 0.00200 AC XY: 1449 AN XY: 725674

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000919

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000700

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74464

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00130

EpiCase AF: 0.00202

EpiControl AF: 0.00262

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	CNGA3: BP4, BP7 -

Achromatopsia 2 Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Apr 15, 2021	- -
Uncertain significance, 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, 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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.3
DANN	Benign	0.66

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: rs139544302; hg19: chr2-98994246;