8-86626069-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_StrongBP6BS1BS2_Supporting

The NM_019098.5(CNGB3):c.1492T>A(p.Leu498Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,611,844 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 3 hom. )

Consequence

CNGB3
NM_019098.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.09

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]

CNGB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1

In a topological_domain Extracellular (size 65) in uniprot entity CNGB3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_019098.5

BP4

Computational evidence support a benign effect (MetaRNN=0.015865922).

BP6

Variant 8-86626069-A-T is Benign according to our data. Variant chr8-86626069-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421450.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00323 (492/152312) while in subpopulation AFR AF= 0.0111 (460/41572). AF 95% confidence interval is 0.0102. There are 1 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5 link	c.1492T>A	p.Leu498Met	missense_variant	Exon 13 of 18	ENST00000320005.6	NP_061971.3	Q9NQW8-1
CNGB3	XM_011517138.3 link	c.1078T>A	p.Leu360Met	missense_variant	Exon 11 of 16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNGB3	ENST00000320005.6 link	c.1492T>A	p.Leu498Met	missense_variant	Exon 13 of 18	1	NM_019098.5	ENSP00000316605.5	Q9NQW8-1
CNGB3	ENST00000681546.1 link	n.1312T>A		non_coding_transcript_exon_variant	Exon 8 of 13
CNGB3	ENST00000681746.1 link	n.1492T>A		non_coding_transcript_exon_variant	Exon 13 of 19			ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

491

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.000862

AC:

216

AN:

250664

Hom.:

AF XY:

0.000642

AC XY:

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000301

AC:

439

AN:

1459532

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

726230

show subpopulations

Gnomad4 AFR exome

AF:

0.00997

Gnomad4 AMR exome

AF:

0.00116

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:

0.00000811

Gnomad4 OTH exome

AF:

0.000730

GnomAD4 genome

AF:

0.00323

AC:

492

AN:

152312

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

242

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.00366

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00104

AC:

126

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L498M variant in the CNGB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The NHLBI ESP Exome Sequencing Project reports L498M was observed in 52/4406 (1.2%) alleles from individuals of African American background, with one homozygous individual reported, indicating it may be a rare benign variant in this population. The L498M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L498M as a variant of uncertain significance. -

Achromatopsia 3;C1855465:Severe early-childhood-onset retinal dystrophy

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Achromatopsia

Benign:1

Nov 11, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CNGB3-related disorder

Benign:1

Oct 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

0.087

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.46

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.53

MVP

0.91

MPC

0.21

ClinPred

0.074

GERP RS

0.29

Varity_R

0.17

gMVP

0.55

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over