rs397515360

Variant names:

• chr8-86643780-AG-A
• rs397515360
• NM_019098.5:c.1148delC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_019098.5(CNGB3):​c.1148delC​(p.Thr383IlefsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00227 in 1,606,146 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329303: Published functional studies demonstrate that if a truncated CNGB3 protein is produced, then the resultant CNG channel complex leads to abnormal cone photoreceptor function (Peng et al., 2003" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T383T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: CNGB3 NM_019098.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:52 O:1
• Conservation: PhyloP100: 6.13
• Publications: 67 publications found

Genes affected

CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

CNGB3 Gene-Disease associations (from GenCC):

• achromatopsia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• CNGB3-related retinopathy

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329303: Published functional studies demonstrate that if a truncated CNGB3 protein is produced, then the resultant CNG channel complex leads to abnormal cone photoreceptor function (Peng et al., 2003; Liu et al., 2013);; SCV000475215: Functional studies showed that the p.Thr383IlefsTer13 variant resulted in a gain-of-function with enhanced channel activity and an increased sensitivity to cell death compared to wild type (Bright et al. 2005; Liu et al. 2013). Expression studies in Xenopus oocytes demonstrated that the p.Thr383IlefsTer13 variant failed to produce a CNGB3 subunit sufficient for normal cone photoreceptor function, and is essentially a null variant (Peng et al. 2003).
• PP5: Variant 8-86643780-AG-A is Pathogenic according to our data. Variant chr8-86643780-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,Unknown,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019098.5. 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
	CNGB3	NM_019098.5	MANE Select	c.1148delC	p.Thr383IlefsTer13	frameshift	Exon 10 of 18	NP_061971.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.1148delC	p.Thr383IlefsTer13	frameshift	Exon 10 of 18	ENSP00000316605.5	Q9NQW8-1
	CNGB3	ENST00000681546.1		n.968delC		non_coding_transcript_exon	Exon 5 of 13
	CNGB3	ENST00000681746.1		n.1148delC		non_coding_transcript_exon	Exon 10 of 19	ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 267 AN: 148896 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000542

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00271

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00311

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00172 AC: 431 AN: 250592 AF XY: 0.00167

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00232 AC: 3384 AN: 1457132 Hom.: 7 Cov.: 31 AF XY: 0.00221 AC XY: 1601 AN XY: 724992

African (AFR) AF: 0.000481 AC: 16 AN: 33280

American (AMR) AF: 0.000763 AC: 34 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.000347 AC: 9 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86176

European-Finnish (FIN) AF: 0.00289 AC: 154 AN: 53336

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.00271 AC: 3006 AN: 1108404

Other (OTH) AF: 0.00213 AC: 128 AN: 60068

GnomAD4 genome AF: 0.00179 AC: 267 AN: 149014 Hom.: 0 Cov.: 30 AF XY: 0.00151 AC XY: 110 AN XY: 72612

African (AFR) AF: 0.000419 AC: 17 AN: 40610

American (AMR) AF: 0.000542 AC: 8 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4662

European-Finnish (FIN) AF: 0.00271 AC: 28 AN: 10332

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00311 AC: 208 AN: 66846

Other (OTH) AF: 0.00197 AC: 4 AN: 2034

Alfa AF: 0.000342 Hom.: 0

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Achromatopsia 3 (19)
12	-	-	not provided (12)
7	-	-	Achromatopsia (7)
4	-	-	Retinal dystrophy (4)
3	-	-	Leber congenital amaurosis (3)
2	-	-	CNGB3-related disorder (2)
1	-	-	Abnormality of the eye (1)
1	-	-	Cone-rod dystrophy (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Optic atrophy (1)
1	-	-	Retinal disorder (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397515360; hg19: chr8-87656008;