rs1052078370

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_019098.5(CNGB3):​c.208C>T​(p.Gln70*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,450 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: 30)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CNGB3
NM_019098.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.306
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 8-86739658-G-A is Pathogenic according to our data. Variant chr8-86739658-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 427681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86739658-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CNGB3NM_019098.5 linkc.208C>T p.Gln70* stop_gained 2/18 ENST00000320005.6 NP_061971.3 Q9NQW8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CNGB3ENST00000320005.6 linkc.208C>T p.Gln70* stop_gained 2/181 NM_019098.5 ENSP00000316605.5 Q9NQW8-1
CNGB3ENST00000519777.1 linkn.190C>T non_coding_transcript_exon_variant 2/42
CNGB3ENST00000681746.1 linkn.208C>T non_coding_transcript_exon_variant 2/19 ENSP00000505959.1 A0A5J6DSN8
ENSG00000254115ENST00000519041.1 linkn.449-21178G>A intron_variant 3

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD3 exomes
AF:
0.00000421
AC:
1
AN:
237748
Hom.:
0
AF XY:
0.00000776
AC XY:
1
AN XY:
128838
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000927
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000213
AC:
3
AN:
1406450
Hom.:
0
Cov.:
40
AF XY:
0.00000286
AC XY:
2
AN XY:
699764
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000279
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Achromatopsia 3 Pathogenic:2
Pathogenic, no assertion criteria providedresearchMolecular Genetics Laboratory, Institute for Ophthalmic ResearchMar 27, 2017- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 15, 2024- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 07, 2023For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 427681). This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 28795510). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln70*) 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
0.49
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Uncertain
0.47
Eigen_PC
Benign
0.17
FATHMM_MKL
Benign
0.23
N
Vest4
0.77
GERP RS
2.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1052078370; hg19: chr8-87751886; API