rs2271041

Positions:

• chr2-98391889-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001298.3(CNGA3):​c.592G>A​(p.Glu198Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,154 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (27 hom.)
• Consequence: CNGA3 NM_001298.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.96

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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001298.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031558275).
• BP6: Variant 2-98391889-G-A is Benign according to our data. Variant chr2-98391889-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1615/152328) while in subpopulation AFR AF= 0.0356 (1479/41568). AF 95% confidence interval is 0.0341. There are 36 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA3	NM_001298.3	c.592G>A	p.Glu198Lys	missense_variant	7/8	ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7	c.592G>A	p.Glu198Lys	missense_variant	7/8	1	NM_001298.3	A1
CNGA3	ENST00000436404.6	c.538G>A	p.Glu180Lys	missense_variant	6/7	1		P4
CNGA3	ENST00000409937.1	n.745G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1609 AN: 152210 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00827

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00363 AC: 912 AN: 251460 Hom.: 12 AF XY: 0.00260 AC XY: 354 AN XY: 135904

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00799

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00155 AC: 2267 AN: 1461826 Hom.: 27 Cov.: 31 AF XY: 0.00138 AC XY: 1002 AN XY: 727214

Gnomad4 AFR exome AF: 0.0377

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0132

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00331

GnomAD4 genome AF: 0.0106 AC: 1615 AN: 152328 Hom.: 36 Cov.: 32 AF XY: 0.0104 AC XY: 778 AN XY: 74494

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00829

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00253 Hom.: 8

Bravo AF: 0.0125

ESP6500AA AF: 0.0415 AC: 183

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00462 AC: 561

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Achromatopsia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Apr 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D;.;D;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T;T;.;T
MetaRNN	Benign	0.0032	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.3	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.046	B;.;B;.
Vest4		0.23
MVP		0.85
MPC		0.11
ClinPred		0.0048	T
GERP RS		4.4
Varity_R		0.047
gMVP		0.33

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: rs2271041; hg19: chr2-99008352;