Genetic Variant CNGA3:c.-271G>A (chr2-98346301-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The ENST00000436404.6(CNGA3):c.-271G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 398,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

CNGA3
ENST00000436404.6 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.445

Publications

0 publications found

Variant links:

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

CNGA3 links:

ENSG00000222000 (HGNC:):

ENSG00000222000 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000483 (119/246462) while in subpopulation SAS AF = 0.00496 (15/3026). AF 95% confidence interval is 0.00305. There are 0 homozygotes in GnomAdExome4. There are 63 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000436404.6. 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.-271G>A		upstream_gene	N/A	NP_001289.1	Q16281-1
	CNGA3	NM_001079878.2		c.-271G>A		upstream_gene	N/A	NP_001073347.1	Q16281-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CNGA3	ENST00000436404.6	TSL:1	c.-271G>A	5_prime_UTR	Exon 1 of 7	ENSP00000410070.2	Q16281-2
CNGA3	ENST00000853268.1		c.-271G>A	5_prime_UTR	Exon 1 of 9	ENSP00000523327.1
CNGA3	ENST00000853267.1		c.-271G>A	5_prime_UTR	Exon 1 of 8	ENSP00000523326.1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000483

AC:

119

AN:

246462

Hom.:

Cov.:

AF XY:

0.000504

AC XY:

AN XY:

124948

show subpopulations

African (AFR)

AF:

0.000139

AC:

AN:

7182

American (AMR)

AF:

0.000942

AC:

AN:

7432

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

9234

East Asian (EAS)

AF:

0.00

AC:

AN:

22896

South Asian (SAS)

AF:

0.00496

AC:

AN:

3026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20830

Middle Eastern (MID)

AF:

0.00309

AC:

AN:

1296

European-Non Finnish (NFE)

AF:

0.000341

AC:

AN:

158198

Other (OTH)

AF:

0.000916

AC:

AN:

16368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41590

American (AMR)

AF:

0.00118

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000540

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Achromatopsia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.1

(source)

DANN

Benign

0.68

PhyloP100

0.45

PromoterAI

-0.0028

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over