rs34839859

Positions:

• chr8-86629043-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_019098.5(CNGB3):​c.1356G>A​(p.Gln452Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,613,948 control chromosomes in the GnomAD database, including 1,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (677 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (595 hom.)
• Consequence: CNGB3 NM_019098.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.09

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 8-86629043-C-T is Benign according to our data. Variant chr8-86629043-C-T is described in ClinVar as [Benign]. Clinvar id is 261082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86629043-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1356G>A	p.Gln452Gln	synonymous_variant	12/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.942G>A	p.Gln314Gln	synonymous_variant	10/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1356G>A	p.Gln452Gln	synonymous_variant	12/18	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.1176G>A		non_coding_transcript_exon_variant	7/13
CNGB3	ENST00000681746.1	n.1356G>A		non_coding_transcript_exon_variant	12/19			ENSP00000505959.1

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7810 AN: 152076 Hom.: 675 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0139 AC: 3492 AN: 250978 Hom.: 269 AF XY: 0.0103 AC XY: 1397 AN XY: 135606

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.00529 AC: 7738 AN: 1461752 Hom.: 595 Cov.: 32 AF XY: 0.00454 AC XY: 3301 AN XY: 727180

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0515 AC: 7837 AN: 152196 Hom.: 677 Cov.: 32 AF XY: 0.0489 AC XY: 3643 AN XY: 74436

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0275 Hom.: 143

Bravo AF: 0.0588

Asia WGS AF: 0.0120 AC: 44 AN: 3476

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Achromatopsia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 02, 2019

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Achromatopsia 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.8
DANN	Benign	0.60

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

Other links and lift over

dbSNP: rs34839859; hg19: chr8-87641271;