rs1554604552

Positions:

• chr8-86576012-TC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_019098.5(CNGB3):​c.2221del​(p.Asp741IlefsTer88) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 NM_019098.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.0310

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.086 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB3	NM_019098.5	c.2221del	p.Asp741IlefsTer88	frameshift_variant	18/18	ENST00000320005.6
CNGB3	XM_011517138.3	c.1807del	p.Asp603IlefsTer88	frameshift_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB3	ENST00000320005.6	c.2221del	p.Asp741IlefsTer88	frameshift_variant	18/18	1	NM_019098.5	P1
CNGB3	ENST00000517327.5	c.276+2676del		intron_variant		3
CNGB3	ENST00000681546.1	n.2041del		non_coding_transcript_exon_variant	13/13
CNGB3	ENST00000681746.1	c.*632del		3_prime_UTR_variant, NMD_transcript_variant	19/19

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Achromatopsia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Mar 27, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2021

This sequence change results in a frameshift in the CNGB3 gene (p.Asp741Ilefs*88). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the CNGB3 protein and extend the protein by 18 additional amino acid residues. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant results in an extension of the CNGB3 protein. Other variant(s) that result in a similarly extended protein product (p.Ser787Alafs*42) have been observed in individuals with CNGB3-related disease (PMID: 28795510). This suggests that these extensions may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 427667). This frameshift has been observed in individual(s) with achromatopsia (PMID: 28795510). This variant is not present in population databases (gnomAD no frequency). -

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: rs1554604552; hg19: chr8-87588240;