chr8-86643810-C-T

Variant names:

• chr8-86643810-C-T
• rs786204762
• NM_019098.5:c.1119G>A

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.Trp373*) 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:6
• 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 rank	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1119G>A	p.Trp373*	stop_gained	Exon 10 of 18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.705G>A	p.Trp235*	stop_gained	Exon 8 of 16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1119G>A	p.Trp373*	stop_gained	Exon 10 of 18	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.939G>A		non_coding_transcript_exon_variant	Exon 5 of 13
CNGB3	ENST00000681746.1	n.1119G>A		non_coding_transcript_exon_variant	Exon 10 of 19			ENSP00000505959.1

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Pathogenic:3

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2017

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 23, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:2

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 15657609, 28795510). ClinVar contains an entry for this variant (Variation ID: 189190). For these reasons, this variant has been classified as Pathogenic. -

Apr 14, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Retinal dystrophy Pathogenic:1

Aug 10, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;