rs372006750

Positions:

• chr8-86625982-C-A
• chr8-86625982-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000320005.6(CNGB3):​c.1578+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 ENST00000320005.6 splice_donor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.48

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86625982-C-A is Pathogenic according to our data. Variant chr8-86625982-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 427704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86625982-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1578+1G>T		splice_donor_variant		ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.1164+1G>T		splice_donor_variant			XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1578+1G>T		splice_donor_variant		1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000681746.1	c.1578+1G>T		splice_donor_variant, NMD_transcript_variant				ENSP00000505959
CNGB3	ENST00000681546.1	n.1398+1G>T		splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28795510) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2021	This sequence change affects a donor splice site in intron 13 of the CNGB3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 15657609). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in many individuals affected with achromatopsia (PMID: 28795510). ClinVar contains an entry for this variant (Variation ID: 427704). -

Achromatopsia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 06, 2021

- -

Achromatopsia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Mar 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs372006750; hg19: chr8-87638210;