rs1553447991

Variant names:

• chr2-98369938-G-C
• rs1553447991
• NM_001298.3:c.-37-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-98369938-G-C
• chr2-98369938-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_001298.3(CNGA3):​c.-37-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000716 in 1,535,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: CNGA3 NM_001298.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.91
• Publications: 1 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: Illumina, G2P, Labcorp Genetics (formerly Invitae)
• 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 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.066187054 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 2-98369938-G-C is Pathogenic according to our data. Variant chr2-98369938-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 503559.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGA3	NM_001298.3	MANE Select	c.-37-1G>C		splice_acceptor intron	N/A	NP_001289.1	Q16281-1
	CNGA3	NM_001079878.2		c.-37-1G>C		splice_acceptor intron	N/A	NP_001073347.1	Q16281-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGA3	ENST00000272602.7	TSL:1 MANE Select	c.-37-1G>C		splice_acceptor intron	N/A	ENSP00000272602.2	Q16281-1
	CNGA3	ENST00000436404.6	TSL:1	c.-37-1G>C		splice_acceptor intron	N/A	ENSP00000410070.2	Q16281-2
	CNGA3	ENST00000853268.1		c.-37-1G>C		splice_acceptor intron	N/A	ENSP00000523327.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000723 AC: 10 AN: 1383746 Hom.: 0 Cov.: 23 AF XY: 0.00000722 AC XY: 5 AN XY: 692256

African (AFR) AF: 0.00 AC: 0 AN: 31910

American (AMR) AF: 0.00 AC: 0 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25570

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51932

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5638

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043712

Other (OTH) AF: 0.000121 AC: 7 AN: 57934

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
1	-	-	Achromatopsia (1)
1	-	-	Achromatopsia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	28
DANN	Uncertain	0.98
PhyloP100		4.9
Mutation Taster		=104/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.96		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553447991; hg19: chr2-98986401;