rs199837807

Variant names:

• chr2-98396039-G-A
• rs199837807
• NM_001298.3:c.869G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-98396039-G-A
• chr2-98396039-G-C
• chr2-98396039-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3 PP5

The NM_001298.3(CNGA3):​c.869G>A​(p.Arg290His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R290C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: CNGA3 NM_001298.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.60
• Publications: 8 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 2-98396039-G-A is Pathogenic according to our data. Variant chr2-98396039-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 503561.

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.869G>A	p.Arg290His	missense	Exon 8 of 8	NP_001289.1
	CNGA3	NM_001079878.2		c.815G>A	p.Arg272His	missense	Exon 7 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.869G>A	p.Arg290His	missense	Exon 8 of 8	ENSP00000272602.2
	CNGA3	ENST00000436404.6	TSL:1	c.815G>A	p.Arg272His	missense	Exon 7 of 7	ENSP00000410070.2
	CNGA3	ENST00000409937.1	TSL:2	n.1022G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251390 AF XY: 0.000140

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000337 AC: 492 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727234

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000424 AC: 471 AN: 1112000

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74458

African (AFR) AF: 0.0000722 AC: 3 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000267 Hom.: 2

Bravo AF: 0.000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Achromatopsia (1)
-	1	-	CNGA3-related disorder (1)
-	1	-	not provided (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.81
MVP		1.0
MPC		0.56
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.90
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs199837807; hg19: chr2-99012502; COSMIC: COSV55625786;