rs886063161

Positions:

• chr8-86654018-TTTTGTAGAAGT-TA
• chr8-86654018-TTTTGTAGAAGT-TT

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_019098.5(CNGB3):​c.886_896delACTTCTACAAAinsT​(p.Thr296fs) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 NM_019098.5 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.62

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_019098.5 (CNGB3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86654019-TTTGTAGAAGT-A is Pathogenic according to our data. Variant chr8-86654019-TTTGTAGAAGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 363876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.886_896delACTTCTACAAAinsT	p.Thr296fs	frameshift_variant, missense_variant	7/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.472_482delACTTCTACAAAinsT	p.Thr158fs	frameshift_variant, missense_variant	5/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.886_896delACTTCTACAAAinsT	p.Thr296fs	frameshift_variant, missense_variant	7/18	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.706_716delACTTCTACAAAinsT		non_coding_transcript_exon_variant	2/13
CNGB3	ENST00000681746.1	n.886_896delACTTCTACAAAinsT		non_coding_transcript_exon_variant	7/19			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CNGB3-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 01, 2024	The CNGB3 c.886_896delinsT variant is predicted to result in a frameshift and premature protein termination (p.Thr296Tyrfs*9). This variant has been reported in the compound heterozygous state in individuals with achromatopsia and/or cone dystrophy (Kohl et al. 2005. PubMed ID: 15657609; Thiadens et al. 2010. PubMed ID: 20079539; Weisschuh et al 2020. PubMed ID: 32531858; Table S2, Del Pozo-Valero et al. 2022. PubMed ID: 35119454). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Frameshift variants in CNGB3 are an established mechanism of disease. Given the evidence, we interpret this variant as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The CNGB3 c.886_896delACTTCTACAAAinsT (p.Thr296TyrfsTer9) variant is a frameshift variant that is predicted to result in premature termination of the protein. The variant has been reported in a total of seven individuals with achromatopsia, including six who were compound heterozygous for the variant and one who was heterozygous without a second identified variant (Kohl et al. 2005). The variant has not been reported in association with Stargardt disease, though Thiadens et al. (2010) reported two unrelated individuals with autosomal recessive progressive cone dystrophy who were both compound heterozygous for the p.Thr296TyrfsTer9 variant and a second null variant. An unaffected parent and an unaffected child of one of the individuals were both heterozygous. The p.Thr296TyrfsTer9 variant was absent from 100 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Thr296TyrfsTer9 variant is classified as pathogenic for CNGB3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Achromatopsia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Mar 27, 2017

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not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2019

The c.886_896del11insT variant in the CNGB3 gene has been reported previously in association with achromatopsia and progressive cone dystrophy (Thiadens et al., 2010; Kohl et al., 2005). This variant causes a frameshift starting with codon Threonine 296, changes this amino acid to a Tyrosine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Thr296TyrfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.886_896del11insT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.886_896del11insT as a pathogenic variant. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886063161; hg19: chr8-87666247;