NM_019098.5:c.892A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T298S) has been classified as Uncertain significance.

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:14

Conservation

PhyloP100: 1.39

Publications

34 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: G2P, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Sel.	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

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	Q9NQW8-1
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	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

GnomAD2 exomes

AF:

0.661

AC:

165844

AN:

251026

AF XY:

0.668

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 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

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

14046

28092

42138

56184

70230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18560

37120

55680

74240

92800

<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:

0.648

AC:

98365

AN:

151910

Hom.:

31980

Cov.:

AF XY:

0.648

AC XY:

48099

AN XY:

74242

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1720

3441

5161

6882

8602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.649

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Achromatopsia 3 (3)

not provided (3)

Achromatopsia (1)

Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

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

PhyloP100

1.4

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

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over