chr8-86654023-T-G

Variant names:

• chr8-86654023-T-G
• rs4961206
• NM_019098.5:c.892A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_019098.5(CNGB3):​c.892A>C​(p.Thr298Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,596,206 control chromosomes in the GnomAD database, including 342,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (31980 hom., cov: 32)
  • Exomes 𝑓: 0.65 (310022 hom.)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.39
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• achromatopsia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• CNGB3-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• achromatopsia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_019098.5
• BP4: Computational evidence support a benign effect (MetaRNN=1.7230448E-6).
• BP6: Variant 8-86654023-T-G is Benign according to our data. Variant chr8-86654023-T-G is described in ClinVar as Benign. ClinVar VariationId is 95929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019098.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	NM_019098.5	MANE Select	c.892A>C	p.Thr298Pro	missense	Exon 7 of 18	NP_061971.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.892A>C	p.Thr298Pro	missense	Exon 7 of 18	ENSP00000316605.5
	CNGB3	ENST00000681546.1		n.712A>C		non_coding_transcript_exon	Exon 2 of 13
	CNGB3	ENST00000681746.1		n.892A>C		non_coding_transcript_exon	Exon 7 of 19	ENSP00000505959.1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98328 AN: 151792 Hom.: 31976 Cov.: 32

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.661 AC: 165844 AN: 251026 AF XY: 0.668

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.796

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.653 AC: 943185 AN: 1444296 Hom.: 310022 Cov.: 30 AF XY: 0.658 AC XY: 473276 AN XY: 719742

African (AFR) AF: 0.625 AC: 20684 AN: 33106

American (AMR) AF: 0.573 AC: 25569 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 18542 AN: 26016

East Asian (EAS) AF: 0.797 AC: 31509 AN: 39538

South Asian (SAS) AF: 0.766 AC: 65754 AN: 85830

European-Finnish (FIN) AF: 0.652 AC: 34788 AN: 53376

Middle Eastern (MID) AF: 0.716 AC: 4105 AN: 5730

European-Non Finnish (NFE) AF: 0.641 AC: 702721 AN: 1096272

Other (OTH) AF: 0.661 AC: 39513 AN: 59770

GnomAD4 genome AF: 0.648 AC: 98365 AN: 151910 Hom.: 31980 Cov.: 32 AF XY: 0.648 AC XY: 48099 AN XY: 74242

African (AFR) AF: 0.632 AC: 26195 AN: 41426

American (AMR) AF: 0.605 AC: 9241 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2447 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4063 AN: 5158

South Asian (SAS) AF: 0.763 AC: 3676 AN: 4818

European-Finnish (FIN) AF: 0.647 AC: 6818 AN: 10540

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43693 AN: 67924

Other (OTH) AF: 0.649 AC: 1367 AN: 2106

Alfa AF: 0.649 Hom.: 115524

Bravo AF: 0.645

TwinsUK AF: 0.642 AC: 2380

ALSPAC AF: 0.640 AC: 2465

ESP6500AA AF: 0.631 AC: 2778

ESP6500EA AF: 0.646 AC: 5551

ExAC AF: 0.665 AC: 80783

Asia WGS AF: 0.705 AC: 2454 AN: 3476

EpiCase AF: 0.645

EpiControl AF: 0.642

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 29, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Achromatopsia 3 Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Achromatopsia Benign:1

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Severe early-childhood-onset retinal dystrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.99	L
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.092
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.0050	B
Vest4		0.14
MPC		0.032
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.28
gMVP		0.77
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4961206; hg19: chr8-87666251; COSMIC: COSV60684928; COSMIC: COSV60684928;