8-86743548-T-C

Position:

chr8-86743548-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 100588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86743548-T-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB3	NM_019098.5 linkuse as main transcript	c.80A>G	p.Asn27Ser	missense_variant	1/18	ENST00000320005.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB3	ENST00000320005.6 linkuse as main transcript	c.80A>G	p.Asn27Ser	missense_variant	1/18	1	NM_019098.5	P1	Q9NQW8-1
	ENST00000519041.1 linkuse as main transcript	n.449-17288T>C		intron_variant, non_coding_transcript_variant		3
CNGB3	ENST00000519777.1 linkuse as main transcript	n.62A>G		non_coding_transcript_exon_variant	1/4	2
CNGB3	ENST00000681746.1 linkuse as main transcript	c.80A>G	p.Asn27Ser	missense_variant, NMD_transcript_variant	1/19

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

GnomAD3 exomes

AF:

0.0185

AC:

4642

AN:

251432

Hom.:

AF XY:

0.0192

AC XY:

2613

AN XY:

135888

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 SAS exome

AF:

0.0141

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

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.00816

Gnomad4 ASJ exome

AF:

0.0389

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0143

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0239

Gnomad4 OTH exome

AF:

0.0209

GnomAD4 genome

AF:

0.0171

AC:

2610

AN:

152318

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1237

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.00993

Gnomad4 ASJ

AF:

0.0412

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.0230

Gnomad4 NFE

AF:

0.0265

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0237

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Achromatopsia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 09, 2019

- -

Severe early-childhood-onset retinal dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

MutationTaster

Benign

1.0

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

Varity_R

0.076

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over