rs1554610284
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_019098.5(CNGB3):c.1426C>T(p.Gln476Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
CNGB3
NM_019098.5 stop_gained
NM_019098.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 8-86628973-G-A is Pathogenic according to our data. Variant chr8-86628973-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 427691.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-86628973-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-86628973-G-A is described in Lovd as [Pathogenic]. Variant chr8-86628973-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGB3 | NM_019098.5 | c.1426C>T | p.Gln476Ter | stop_gained | 12/18 | ENST00000320005.6 | |
CNGB3 | XM_011517138.3 | c.1012C>T | p.Gln338Ter | stop_gained | 10/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGB3 | ENST00000320005.6 | c.1426C>T | p.Gln476Ter | stop_gained | 12/18 | 1 | NM_019098.5 | P1 | |
CNGB3 | ENST00000681546.1 | n.1246C>T | non_coding_transcript_exon_variant | 7/13 | |||||
CNGB3 | ENST00000681746.1 | c.1426C>T | p.Gln476Ter | stop_gained, NMD_transcript_variant | 12/19 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461726Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727162
GnomAD4 exome
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10
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32
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5
AN XY:
727162
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
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 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2021 | This premature translational stop signal has been observed in individual(s) with clinical features of achromatopsia (PMID: 28341476, 28795510). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln476*) 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). ClinVar contains an entry for this variant (Variation ID: 427691). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at