chr2-98391889-G-A

Variant names:

• chr2-98391889-G-A
• rs2271041
• NM_001298.3:c.592G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 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. 16/21 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:6
• Conservation: PhyloP100: 1.96
• Publications: 11 publications found

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]

CNGA3 Gene-Disease associations (from GenCC):

• achromatopsia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia
• CNGA3-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• achromatopsia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001298.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 105 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Trascript score misZ: 0.49806 (below the threshold of 3.09). GenCC associations: The gene is linked to achromatopsia 2, CNGA3-related retinopathy, cone-rod dystrophy, achromatopsia.
• 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001298.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGA3	NM_001298.3	MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 7 of 8	NP_001289.1
	CNGA3	NM_001079878.2		c.538G>A	p.Glu180Lys	missense	Exon 6 of 7	NP_001073347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGA3	ENST00000272602.7	TSL:1 MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 7 of 8	ENSP00000272602.2
	CNGA3	ENST00000436404.6	TSL:1	c.538G>A	p.Glu180Lys	missense	Exon 6 of 7	ENSP00000410070.2
	CNGA3	ENST00000409937.1	TSL:2	n.745G>A		non_coding_transcript_exon	Exon 7 of 8

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

GnomAD2 exomes AF: 0.00363 AC: 912 AN: 251460 AF XY: 0.00260

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 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

African (AFR) AF: 0.0377 AC: 1262 AN: 33478

American (AMR) AF: 0.00244 AC: 109 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0132 AC: 526 AN: 39698

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86252

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53400

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111980

Other (OTH) AF: 0.00331 AC: 200 AN: 60394

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

African (AFR) AF: 0.0356 AC: 1479 AN: 41568

American (AMR) AF: 0.00399 AC: 61 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00829 AC: 43 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68036

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00285 Hom.: 13

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Achromatopsia 2 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0032	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.24
Sift	Benign	0.39	T
Sift4G	Benign	0.73	T
Polyphen		0.046	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2271041; hg19: chr2-99008352;