8-86644689-A-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_019098.5(CNGB3):c.991-3T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,523,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CNGB3
NM_019098.5 splice_region, intron

Scores

Splicing: ADA: 0.9459

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: -0.435

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.

PP5

Variant 8-86644689-A-C is Pathogenic according to our data. Variant chr8-86644689-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 188827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5 link	c.991-3T>G		splice_region_variant, intron_variant	Intron 8 of 17	ENST00000320005.6	NP_061971.3	Q9NQW8-1
CNGB3	XM_011517138.3 link	c.577-3T>G		splice_region_variant, intron_variant	Intron 6 of 15		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNGB3	ENST00000320005.6 link	c.991-3T>G	splice_region_variant, intron_variant	Intron 8 of 17	1	NM_019098.5	ENSP00000316605.5	Q9NQW8-1
CNGB3	ENST00000681546.1 link	n.811-3T>G	splice_region_variant, intron_variant	Intron 3 of 12
CNGB3	ENST00000681746.1 link	n.991-3T>G	splice_region_variant, intron_variant	Intron 8 of 18			ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.0000134

AC:

AN:

224156

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000191

Gnomad OTH exome

AF:

0.000192

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1372648

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

680332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30672

American (AMR)

AF:

0.00

AC:

AN:

37626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23426

East Asian (EAS)

AF:

0.00

AC:

AN:

37722

South Asian (SAS)

AF:

0.00

AC:

AN:

68508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1065288

Other (OTH)

AF:

0.00

AC:

AN:

55846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151212

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41350

American (AMR)

AF:

0.00

AC:

AN:

15112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67398

Other (OTH)

AF:

0.000482

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000428

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 3

Pathogenic:3

Feb 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CNGB3 c.991-3T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site. One predict the variant weakens a 3' acceptor site. Four predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 224156 control chromosomes. c.991-3T>G has been reported in the literature in multiple individuals affected with Achromatopsia and Progressive Cone Dystrophy (Thiadens_CNGB3_Opth_2010, Mayer_2017, etc.). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 13, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 27, 2017

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 8 of the CNGB3 gene. It does not directly change the encoded amino acid sequence of the CNGB3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs773372519, gnomAD 0.001%). This variant has been observed in individual(s) with autosomal recessive achromatopsia or cone dystrophy (PMID: 15459792, 20079539, 28795510). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188827). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:2

Jan 01, 2015

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis

Pathogenic:1

Sep 01, 2016

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Benign

0.29

PhyloP100

-0.43

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -1

DS_AL_spliceai

0.95

Position offset: -3

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