rs1554614038

Variant names:

• chr8-86667094-G-GC
• rs1554614038
• NM_019098.5:c.682dupG

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.682dupG​(p.Ala228GlyfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CNGB3 NM_019098.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.01

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 8-86667094-G-GC is Pathogenic according to our data. Variant chr8-86667094-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 427651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.682dupG	p.Ala228GlyfsTer3	frameshift_variant	Exon 6 of 18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.268dupG	p.Ala90GlyfsTer3	frameshift_variant	Exon 4 of 16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.682dupG	p.Ala228GlyfsTer3	frameshift_variant	Exon 6 of 18	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681746.1	n.682dupG		non_coding_transcript_exon_variant	Exon 6 of 19			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461704 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Pathogenic:2

Nov 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CNGB3 c.682dupG (p.Ala228GlyfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251368 control chromosomes. c.682dupG has been reported in the literature in individuals affected with Achromatopsia (example: Mayer_2017). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28795510). ClinVar contains an entry for this variant (Variation ID: 427651). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 27, 2017

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Aug 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC 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: 427651). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ala228Glyfs*3) 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). -

Computational scores

Source: dbNSFP v4.3

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: rs1554614038; hg19: chr8-87679322;