rs3735972

Variant names:

• chr8-86575970-T-C
• rs3735972
• NM_019098.5:c.2264A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019098.5(CNGB3):​c.2264A>G​(p.Glu755Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0888 in 1,613,852 control chromosomes in the GnomAD database, including 6,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.082 (575 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6088 hom.)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.315
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027657747).
• BP6: Variant 8-86575970-T-C is Benign according to our data. Variant chr8-86575970-T-C is described in ClinVar as Benign. ClinVar VariationId is 166899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0928 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.2264A>G	p.Glu755Gly	missense	Exon 18 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.2264A>G	p.Glu755Gly	missense	Exon 18 of 18	ENSP00000316605.5
	CNGB3	ENST00000681546.1		n.2084A>G		non_coding_transcript_exon	Exon 13 of 13
	CNGB3	ENST00000681746.1		n.*675A>G		non_coding_transcript_exon	Exon 19 of 19	ENSP00000505959.1

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12513 AN: 152144 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.0702

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0616

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.0997

Gnomad SAS AF: 0.0744

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.0718

GnomAD2 exomes AF: 0.0867 AC: 21800 AN: 251370 AF XY: 0.0869

Gnomad AFR exome AF: 0.0738

Gnomad AMR exome AF: 0.0780

Gnomad ASJ exome AF: 0.0600

Gnomad EAS exome AF: 0.0878

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0909

Gnomad OTH exome AF: 0.0860

GnomAD4 exome AF: 0.0895 AC: 130776 AN: 1461588 Hom.: 6088 Cov.: 32 AF XY: 0.0889 AC XY: 64611 AN XY: 727118

African (AFR) AF: 0.0687 AC: 2300 AN: 33474

American (AMR) AF: 0.0780 AC: 3485 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0595 AC: 1554 AN: 26134

East Asian (EAS) AF: 0.114 AC: 4507 AN: 39696

South Asian (SAS) AF: 0.0796 AC: 6862 AN: 86230

European-Finnish (FIN) AF: 0.109 AC: 5839 AN: 53412

Middle Eastern (MID) AF: 0.0593 AC: 342 AN: 5768

European-Non Finnish (NFE) AF: 0.0903 AC: 100439 AN: 1111782

Other (OTH) AF: 0.0902 AC: 5448 AN: 60384

GnomAD4 genome AF: 0.0823 AC: 12526 AN: 152264 Hom.: 575 Cov.: 32 AF XY: 0.0830 AC XY: 6177 AN XY: 74444

African (AFR) AF: 0.0702 AC: 2916 AN: 41558

American (AMR) AF: 0.0616 AC: 942 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 216 AN: 3468

East Asian (EAS) AF: 0.0999 AC: 517 AN: 5176

South Asian (SAS) AF: 0.0755 AC: 364 AN: 4820

European-Finnish (FIN) AF: 0.112 AC: 1189 AN: 10596

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6136 AN: 68028

Other (OTH) AF: 0.0724 AC: 153 AN: 2112

Alfa AF: 0.0856 Hom.: 1826

Bravo AF: 0.0790

TwinsUK AF: 0.0814 AC: 302

ALSPAC AF: 0.0921 AC: 355

ESP6500AA AF: 0.0704 AC: 310

ESP6500EA AF: 0.0864 AC: 743

ExAC AF: 0.0872 AC: 10593

Asia WGS AF: 0.118 AC: 409 AN: 3478

EpiCase AF: 0.0829

EpiControl AF: 0.0806

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Achromatopsia Benign:1

Sep 16, 2020

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.

Achromatopsia 3 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	0.080
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.8
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.32
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Benign	0.032	D
Sift4G	Benign	0.23	T
Polyphen		0.12	B
Vest4		0.016
MPC		0.033
ClinPred		0.0054	T
GERP RS		3.0
Varity_R		0.072
gMVP		0.17
Mutation Taster		=97/3	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: rs3735972; hg19: chr8-87588198; COSMIC: COSV100181308;