rs1554604525

Positions:

• chr8-86575874-CT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000320005.6(CNGB3):​c.2359del​(p.Ser787AlafsTer42) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S787S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 ENST00000320005.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.31

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 5 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 0.0292 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86575874-CT-C is Pathogenic according to our data. Variant chr8-86575874-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 427668.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-86575874-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.2359del	p.Ser787AlafsTer42	frameshift_variant	18/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.1945del	p.Ser649AlafsTer42	frameshift_variant	16/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.2359del	p.Ser787AlafsTer42	frameshift_variant	18/18	1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000517327.5	c.276+2814del		intron_variant		3		ENSP00000428329
CNGB3	ENST00000681546.1	n.2179del		non_coding_transcript_exon_variant	13/13
CNGB3	ENST00000681746.1	c.*770del		3_prime_UTR_variant, NMD_transcript_variant	19/19			ENSP00000505959

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Achromatopsia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Mar 27, 2017

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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: rs1554604525; hg19: chr8-87588102;