rs147876778

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_019098.5(CNGB3):c.1208G>A(p.Arg403Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,558 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R403R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 68 hom. )

Consequence

CNGB3
NM_019098.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4B:9

Conservation

PhyloP100: 2.14

Publications

36 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: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00217 (330/152224) while in subpopulation SAS AF = 0.0307 (148/4820). AF 95% confidence interval is 0.0267. There are 5 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 5 AR,AD,Unknown gene

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.1208G>A	p.Arg403Gln	missense	Exon 11 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.1208G>A	p.Arg403Gln	missense	Exon 11 of 18	ENSP00000316605.5	Q9NQW8-1
CNGB3	ENST00000681546.1		n.1028G>A		non_coding_transcript_exon	Exon 6 of 13
CNGB3	ENST00000681746.1		n.1208G>A		non_coding_transcript_exon	Exon 11 of 19	ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00458

AC:

1150

AN:

251014

AF XY:

0.00598

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00323

AC:

4711

AN:

1460334

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2981

AN XY:

726498

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33430

American (AMR)

AF:

0.000582

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

26120

East Asian (EAS)

AF:

0.00497

AC:

197

AN:

39614

South Asian (SAS)

AF:

0.0282

AC:

2426

AN:

86168

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.0105

AC:

AN:

4878

European-Non Finnish (NFE)

AF:

0.00153

AC:

1705

AN:

1111764

Other (OTH)

AF:

0.00372

AC:

224

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

235

470

705

940

1175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00217

AC:

330

AN:

152224

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41554

American (AMR)

AF:

0.000720

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00348

AC:

AN:

5176

South Asian (SAS)

AF:

0.0307

AC:

148

AN:

4820

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00194

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00509

AC:

618

Asia WGS

AF:

0.0120

AC:

AN:

3470

EpiCase

AF:

0.00278

EpiControl

AF:

0.00219

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Achromatopsia (3)

Achromatopsia 3 (3)

not specified (2)

Severe early-childhood-onset retinal dystrophy (2)

Abnormality of the eye (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.015

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.5

PhyloP100

2.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.71

Sift

Uncertain

0.021

Sift4G

Uncertain

0.041

Polyphen

0.97

Vest4

0.90

MVP

0.97

MPC

0.19

ClinPred

0.035

GERP RS

5.1

Varity_R

0.45

gMVP

0.92

Mutation Taster

=90/10

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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