GeneBe

rs765574129

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_019098.5(CNGB3):​c.1190_1192delGTT​(p.Cys397del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C397C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CNGB3
NM_019098.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.32

Publications

1 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_019098.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 8-86632879-TAAC-T is Pathogenic according to our data. Variant chr8-86632879-TAAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 427657.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CNGB3NM_019098.5 linkc.1190_1192delGTT p.Cys397del disruptive_inframe_deletion Exon 11 of 18 ENST00000320005.6 NP_061971.3 Q9NQW8-1
CNGB3XM_011517138.3 linkc.776_778delGTT p.Cys259del disruptive_inframe_deletion Exon 9 of 16 XP_011515440.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CNGB3ENST00000320005.6 linkc.1190_1192delGTT p.Cys397del disruptive_inframe_deletion Exon 11 of 18 1 NM_019098.5 ENSP00000316605.5 Q9NQW8-1
CNGB3ENST00000681546.1 linkn.1010_1012delGTT non_coding_transcript_exon_variant Exon 6 of 13
CNGB3ENST00000681746.1 linkn.1190_1192delGTT non_coding_transcript_exon_variant Exon 11 of 19 ENSP00000505959.1 A0A5J6DSN8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250880
AF XY:
0.00000737
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460106
Hom.:
0
AF XY:
0.00000275
AC XY:
2
AN XY:
726378
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33422
American (AMR)
AF:
0.00
AC:
0
AN:
44682
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39604
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86182
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4756
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111694
Other (OTH)
AF:
0.00
AC:
0
AN:
60246
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.350
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Achromatopsia Pathogenic:1
Jan 09, 2020
Molecular Genetics Laboratory, Institute for Ophthalmic Research
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Achromatopsia 3 Uncertain:1
Mar 27, 2017
Molecular Genetics Laboratory, Institute for Ophthalmic Research
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
9.3
Mutation Taster
=57/43
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs765574129; hg19: chr8-87645107; API