2-98377671-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001298.3(CNGA3):c.102-16A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,607,010 control chromosomes in the GnomAD database, including 6,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (566 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5633 hom.)
• Consequence: CNGA3 NM_001298.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.592

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-98377671-A-G is Benign according to our data. Variant chr2-98377671-A-G is described in ClinVar as [Benign]. Clinvar id is 257961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-98377671-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA3	NM_001298.3	c.102-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7	c.102-16A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001298.3	A1
CNGA3	ENST00000436404.6	c.102-16A>G		splice_polypyrimidine_tract_variant, intron_variant		1		P4
CNGA3	ENST00000409937.1	n.90-16A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12026 AN: 152110 Hom.: 565 Cov.: 33

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.0722

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0748

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0898

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.0828 AC: 20163 AN: 243392 Hom.: 950 AF XY: 0.0841 AC XY: 11062 AN XY: 131500

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.0489

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.0607

Gnomad FIN exome AF: 0.0744

Gnomad NFE exome AF: 0.0879

Gnomad OTH exome AF: 0.0955

GnomAD4 exome AF: 0.0852 AC: 123923 AN: 1454782 Hom.: 5633 Cov.: 30 AF XY: 0.0852 AC XY: 61647 AN XY: 723200

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.0514

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.0612

Gnomad4 FIN exome AF: 0.0716

Gnomad4 NFE exome AF: 0.0856

Gnomad4 OTH exome AF: 0.0942

GnomAD4 genome AF: 0.0791 AC: 12035 AN: 152228 Hom.: 566 Cov.: 33 AF XY: 0.0790 AC XY: 5875 AN XY: 74414

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.0748

Gnomad4 NFE AF: 0.0898

Gnomad4 OTH AF: 0.0885

Alfa AF: 0.0722 Hom.: 189

Bravo AF: 0.0797

Asia WGS AF: 0.122 AC: 425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Achromatopsia 2 Benign:1

Benign, no assertion criteria provided

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Apr 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.9
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2279859; hg19: chr2-98994134;