8-86654023-T-G

Position:

chr8-86654023-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

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. 14/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.39

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:

CNGB3 (HGNC:):

CNGB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 30) in uniprot entity CNGB3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 id is 95929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86654023-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5 linkuse as main transcript	c.892A>C	p.Thr298Pro	missense_variant	7/18	ENST00000320005.6	NP_061971.3	Q9NQW8-1
CNGB3	XM_011517138.3 linkuse as main transcript	c.478A>C	p.Thr160Pro	missense_variant	5/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CNGB3	ENST00000320005.6 linkuse as main transcript	c.892A>C	p.Thr298Pro	missense_variant	7/18	1	NM_019098.5	ENSP00000316605.5	Q9NQW8-1
CNGB3	ENST00000681546.1 linkuse as main transcript	n.712A>C		non_coding_transcript_exon_variant	2/13
CNGB3	ENST00000681746.1 linkuse as main transcript	n.892A>C		non_coding_transcript_exon_variant	7/19			ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98328

AN:

151792

Hom.:

31976

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.661

AC:

165844

AN:

251026

Hom.:

55316

AF XY:

0.668

AC XY:

90668

AN XY:

135696

show subpopulations

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 SAS exome

AF:

0.765

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.:

AF XY:

0.658

AC XY:

473276

AN XY:

719742

show subpopulations

Gnomad4 AFR exome

AF:

0.625

Gnomad4 AMR exome

AF:

0.573

Gnomad4 ASJ exome

AF:

0.713

Gnomad4 EAS exome

AF:

0.797

Gnomad4 SAS exome

AF:

0.766

Gnomad4 FIN exome

AF:

0.652

Gnomad4 NFE exome

AF:

0.641

Gnomad4 OTH exome

AF:

0.661

GnomAD4 genome

AF:

0.648

AC:

98365

AN:

151910

Hom.:

31980

Cov.:

AF XY:

0.648

AC XY:

48099

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.632

Gnomad4 AMR

AF:

0.605

Gnomad4 ASJ

AF:

0.705

Gnomad4 EAS

AF:

0.788

Gnomad4 SAS

AF:

0.763

Gnomad4 FIN

AF:

0.647

Gnomad4 NFE

AF:

0.643

Gnomad4 OTH

AF:

0.649

Alfa

AF:

0.650

Hom.:

60932

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:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Achromatopsia 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Achromatopsia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 18, 2019

- -

Severe early-childhood-onset retinal dystrophy

Benign:1

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 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

0.076

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0000017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.99

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.1

REVEL

Benign

0.092

Sift

Benign

0.27

Sift4G

Benign

0.27

Polyphen

0.0050

Vest4

0.14

MPC

0.032

ClinPred

0.013

GERP RS

4.2

Varity_R

0.28

gMVP

0.77

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