rs6471482

Positions:

• chr8-86667075-A-C
• chr8-86667075-A-G
• chr8-86667075-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_019098.5(CNGB3):​c.702T>G​(p.Cys234Trp) variant causes a missense change. The variant allele was found at a frequency of 0.857 in 1,613,820 control chromosomes in the GnomAD database, including 594,751 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60939 hom., cov: 31)
  • Exomes 𝑓: 0.85 (533812 hom.)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.03

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 Benign. Variant got -18 ACMG points.

• PM1: In a helix (size 25) in uniprot entity CNGB3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_019098.5
• BP4: Computational evidence support a benign effect (MetaRNN=6.7922883E-7).
• BP6: Variant 8-86667075-A-C is Benign according to our data. Variant chr8-86667075-A-C is described in ClinVar as [Benign]. Clinvar id is 261090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86667075-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.702T>G	p.Cys234Trp	missense_variant	6/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.288T>G	p.Cys96Trp	missense_variant	4/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.702T>G	p.Cys234Trp	missense_variant	6/18	1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000681746.1	c.702T>G	p.Cys234Trp	missense_variant, NMD_transcript_variant	6/19			ENSP00000505959

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135739 AN: 152048 Hom.: 60875 Cov.: 31

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.867

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.904

GnomAD3 exomes AF: 0.892 AC: 224365 AN: 251402 Hom.: 100674 AF XY: 0.893 AC XY: 121341 AN XY: 135872

Gnomad AFR exome AF: 0.975

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.982

Gnomad FIN exome AF: 0.865

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.873

GnomAD4 exome AF: 0.853 AC: 1246827 AN: 1461654 Hom.: 533812 Cov.: 58 AF XY: 0.857 AC XY: 622898 AN XY: 727124

Gnomad4 AFR exome AF: 0.976

Gnomad4 AMR exome AF: 0.929

Gnomad4 ASJ exome AF: 0.867

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.982

Gnomad4 FIN exome AF: 0.863

Gnomad4 NFE exome AF: 0.829

Gnomad4 OTH exome AF: 0.873

GnomAD4 genome AF: 0.893 AC: 135864 AN: 152166 Hom.: 60939 Cov.: 31 AF XY: 0.897 AC XY: 66690 AN XY: 74372

Gnomad4 AFR AF: 0.971

Gnomad4 AMR AF: 0.906

Gnomad4 ASJ AF: 0.867

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.984

Gnomad4 FIN AF: 0.874

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.905

Alfa AF: 0.850 Hom.: 133336

Bravo AF: 0.899

TwinsUK AF: 0.824 AC: 3057

ALSPAC AF: 0.831 AC: 3202

ESP6500AA AF: 0.967 AC: 4259

ESP6500EA AF: 0.833 AC: 7168

ExAC AF: 0.894 AC: 108602

Asia WGS AF: 0.981 AC: 3411 AN: 3478

EpiCase AF: 0.843

EpiControl AF: 0.839

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Achromatopsia 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26106334) -

Achromatopsia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 16, 2019

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.50
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	6.8e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.4	N
MutationTaster	Benign	0.0015	P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	13	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.032
ClinPred		0.0094	T
GERP RS		5.5
Varity_R		0.34
gMVP		0.79

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: rs6471482; hg19: chr8-87679303;