8-86743548-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019098.5(CNGB3):c.80A>G(p.Asn27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,020 control chromosomes in the GnomAD database, including 471 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N27H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 26 hom., cov: 32)

Exomes 𝑓: 0.022 ( 445 hom. )

Consequence

CNGB3
NM_019098.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.308

Publications

13 publications found

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 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)

CNGB3 links:

ENSG00000253778 (HGNC:58258):

ENSG00000253778 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039350986).

BP6

Variant 8-86743548-T-C is Benign according to our data. Variant chr8-86743548-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 100588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2610/152318) while in subpopulation NFE AF = 0.0265 (1801/68032). AF 95% confidence interval is 0.0255. There are 26 homozygotes in GnomAd4. There are 1237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5 link	c.80A>G	p.Asn27Ser	missense_variant	Exon 1 of 18	ENST00000320005.6	NP_061971.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6 link	c.80A>G	p.Asn27Ser	missense_variant	Exon 1 of 18	1	NM_019098.5	ENSP00000316605.5

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2611

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.0412

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0265

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0185

AC:

4642

AN:

251432

AF XY:

0.0192

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00749

Gnomad ASJ exome

AF:

0.0400

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0244

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0209

GnomAD4 exome

AF:

0.0220

AC:

32091

AN:

1461702

Hom.:

445

Cov.:

AF XY:

0.0219

AC XY:

15954

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00326

AC:

109

AN:

33480

American (AMR)

AF:

0.00816

AC:

365

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

1017

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.0143

AC:

1236

AN:

86254

European-Finnish (FIN)

AF:

0.0256

AC:

1365

AN:

53420

Middle Eastern (MID)

AF:

0.0225

AC:

130

AN:

5768

European-Non Finnish (NFE)

AF:

0.0239

AC:

26603

AN:

1111856

Other (OTH)

AF:

0.0209

AC:

1264

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1726

3452

5177

6903

8629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0171

AC:

2610

AN:

152318

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1237

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41568

American (AMR)

AF:

0.00993

AC:

152

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0412

AC:

143

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0106

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0230

AC:

244

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0265

AC:

1801

AN:

68032

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

127

254

380

507

634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0224

Hom.:

167

Bravo

AF:

0.0151

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0248

AC:

213

ExAC

AF:

0.0181

AC:

2202

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0278

EpiControl

AF:

0.0252

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

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

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Achromatopsia

Benign:1

Sep 09, 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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Achromatopsia 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.31

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.059

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.31

PrimateAI

Benign

0.32

PROVEAN

Benign

0.090

REVEL

Benign

0.0060

Sift

Benign

0.31

Sift4G

Benign

0.48

Polyphen

0.0010

Vest4

0.11

MPC

0.024

ClinPred

0.0076

GERP RS

0.23

PromoterAI

0.0016

Neutral

(source)

Varity_R

0.076

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over