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rs765574129

chr8-86632879-TAAC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate

The NM_019098.5(CNGB3):c.1190_1192del(p.Cys397del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 9.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a helix (size 12) in uniprot entity CNGB3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_019098.5
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM4
?
    PM4 - Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Nonframeshift variant in NON repetitive region in NM_019098.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-86632879-TAAC-T is Pathogenic according to our data. Variant chr8-86632879-TAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 427657.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-86632879-TAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNGB3NM_019098.5 linkuse as main transcriptc.1190_1192del p.Cys397del inframe_deletion 11/18 ENST00000320005.6
CNGB3XM_011517138.3 linkuse as main transcriptc.776_778del p.Cys259del inframe_deletion 9/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNGB3ENST00000320005.6 linkuse as main transcriptc.1190_1192del p.Cys397del inframe_deletion 11/181 NM_019098.5 P1Q9NQW8-1
CNGB3ENST00000681546.1 linkuse as main transcriptn.1010_1012del non_coding_transcript_exon_variant 6/13
CNGB3ENST00000681746.1 linkuse as main transcriptc.1190_1192del p.Cys397del inframe_deletion, NMD_transcript_variant 11/19

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250880
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135600
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 SAS 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
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

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

Submissions by phenotype

Achromatopsia Pathogenic:1
Pathogenic, criteria provided, single submitterresearchMolecular Genetics Laboratory, Institute for Ophthalmic ResearchJan 09, 2020- -
Achromatopsia 3 Uncertain:1
Uncertain significance, no assertion criteria providedresearchMolecular Genetics Laboratory, Institute for Ophthalmic ResearchMar 27, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs765574129; hg19: chr8-87645107; API