rs147876778

chr8-86632864-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BS1_Supporting BS2

The NM_019098.5(CNGB3):c.1208G>A(p.Arg403Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,558 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R403R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (68 hom.)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3 B:8
• Conservation: PhyloP100: 2.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a helix (size 12) in uniprot entity CNGB3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_019098.5
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00217 (330/152224) while in subpopulation SAS AF= 0.0307 (148/4820). AF 95% confidence interval is 0.0267. There are 5 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB3	NM_019098.5	c.1208G>A	p.Arg403Gln	missense_variant	11/18	ENST00000320005.6
CNGB3	XM_011517138.3	c.794G>A	p.Arg265Gln	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB3	ENST00000320005.6	c.1208G>A	p.Arg403Gln	missense_variant	11/18	1	NM_019098.5	P1
CNGB3	ENST00000681546.1	n.1028G>A		non_coding_transcript_exon_variant	6/13
CNGB3	ENST00000681746.1	c.1208G>A	p.Arg403Gln	missense_variant, NMD_transcript_variant	11/19

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152106 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00458 AC: 1150 AN: 251014 Hom.: 24 AF XY: 0.00598 AC XY: 812 AN XY: 135674

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00158

Gnomad SAS exome AF: 0.0273

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00323 AC: 4711 AN: 1460334 Hom.: 68 Cov.: 31 AF XY: 0.00410 AC XY: 2981 AN XY: 726498

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00497

Gnomad4 SAS exome AF: 0.0282

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00372

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152224 Hom.: 5 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74424

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.0307

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00181 Hom.: 2

Bravo AF: 0.00141

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00509 AC: 618

Asia WGS AF: 0.0120 AC: 41 AN: 3470

EpiCase AF: 0.00278

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CNGB3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	See Variant Classification Assertion Criteria. -

Achromatopsia Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 20, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Achromatopsia 3 Pathogenic:1 Benign:1

Likely pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: CNGB3 c.1208G>A (p.Arg403Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251014 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 24 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Biallelic mutations in CNBG3 cause autosomal recessive Achromatopsia. However, the c.1208G>A variant has been reported in patients who present with a highly variable range of clinical findings from mild macular dystrophy to severe cone dystrophy with near complete loss of cone function (eg. Michaelides_2004, Lin_2017, Greenberg_2014, Jinda_2021, Burkard_2018, Mayer_2017). One in depth exploration of a large cohort of patients with the variant suggests the variant is a hypomorphic mutation that may cause relatively mild and late-onset or subclinical retinal disease in the homozygous state and may be a cause of digenic triallelic disease due to the correlation of disease severity with CNGB3 and CNGA3 genoytpes (Burkard_2018). Consistent with the clinical findings, a Cngb3-R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3/) mice to obtain triallelic Cnga3+/ Cngb3R403Q/R403Q mutants showed striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice (Burkard_2018). A different functional study found that co-expression of WT CNGA3 and mutant CNGB3/p.R403Q in Xenopus oocytes resulted in formation of heterotetrameric CNG channels with normal surface expression, but increased apparent ligand sensitivity and increased outward rectification, suggesting a gain-of-function mechanism (Bright_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16379026, 30418171, 24504161, 32869108, 28418496, 28795510, 15161866). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Six submitters classified the variant as benign/likely benign, four classified the variant as pathogenic/likely pathogenic, and two classified it as VUS. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2015	- -

Severe early-childhood-onset retinal dystrophy Benign:2

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Arg403Gln variant in CNGB3 has been identified in 3 homozygous Pakistani individuals with progressive cone dystrophy, 1 homozygous Pakistani individual with complete achromatopsia, and in the heterozygous state in 1 individual with progressive cone dystrophy, segregated with eye disease in 4 relatives from 1 family (PMID: 15161866, 24504161), and has been identified in >2% of South Asian chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg403Gln variant may slightly impact protein function (PMID: 16379026). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive progressive cone dystrophy. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Abnormality of the eye Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jun 18, 2017

- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Sep 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.041	D
Polyphen		0.97	D
Vest4		0.90
MVP		0.97
MPC		0.19
ClinPred		0.035	T
GERP RS		5.1
Varity_R		0.45
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 29

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

Publications

LitVar

Other links and lift over

dbSNP: rs147876778; hg19: chr8-87645092; COSMIC: COSV60692878;