rs786204498

chr8-86743516-G-A

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.112C>T(p.Gln38Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q38Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 NM_019098.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.14

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]

(HGNC:):

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 8-86743516-G-A is Pathogenic according to our data. Variant chr8-86743516-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86743516-G-A is described in Lovd as [Pathogenic]. Variant chr8-86743516-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB3	NM_019098.5	c.112C>T	p.Gln38Ter	stop_gained	1/18	ENST00000320005.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB3	ENST00000320005.6	c.112C>T	p.Gln38Ter	stop_gained	1/18	1	NM_019098.5	P1
	ENST00000519041.1	n.449-17320G>A		intron_variant, non_coding_transcript_variant		3
CNGB3	ENST00000519777.1	n.94C>T		non_coding_transcript_exon_variant	1/4	2
CNGB3	ENST00000681746.1	c.112C>T	p.Gln38Ter	stop_gained, NMD_transcript_variant	1/19

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 11, 2014	- -

Achromatopsia Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Mar 20, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188828). This premature translational stop signal has been observed in individual(s) with achrompatopsia (PMID: 15657609, 28795510, 30418171). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln38*) 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Benign	0.063
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.18	N
MutationTaster	Benign	1.0	A
Vest4		0.35
GERP RS		2.9

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: rs786204498; hg19: chr8-87755744;