rs786204762

chr8-86643810-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_019098.5(CNGB3):c.1119G>A(p.Trp373Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,412 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CNGB3 NM_019098.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86643810-C-T is Pathogenic according to our data. Variant chr8-86643810-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86643810-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB3	NM_019098.5	c.1119G>A	p.Trp373Ter	stop_gained	10/18	ENST00000320005.6
CNGB3	XM_011517138.3	c.705G>A	p.Trp235Ter	stop_gained	8/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB3	ENST00000320005.6	c.1119G>A	p.Trp373Ter	stop_gained	10/18	1	NM_019098.5	P1
CNGB3	ENST00000681546.1	n.939G>A		non_coding_transcript_exon_variant	5/13
CNGB3	ENST00000681746.1	c.1119G>A	p.Trp373Ter	stop_gained, NMD_transcript_variant	10/19

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457412 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725080

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 23, 2015	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2016	The W373X pathogenic variant in the CNGB3 gene has been reported previously in the homozygous state in an individual with achromatopsia (Kohl et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W373X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we interpret W373X as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189190). This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 15657609, 28795510). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp373*) in the CNGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 28795510). -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		4.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204762; hg19: chr8-87656038;