rs3735970

Positions:

• chr8-86576020-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019098.5(CNGB3):​c.2214A>G​(p.Glu738=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,610,886 control chromosomes in the GnomAD database, including 6,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (575 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6080 hom.)
• Consequence: CNGB3 NM_019098.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.922

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-86576020-T-C is Benign according to our data. Variant chr8-86576020-T-C is described in ClinVar as [Benign]. Clinvar id is 166903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86576020-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.922 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB3	NM_019098.5	c.2214A>G	p.Glu738=	synonymous_variant	18/18	ENST00000320005.6
CNGB3	XM_011517138.3	c.1800A>G	p.Glu600=	synonymous_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB3	ENST00000320005.6	c.2214A>G	p.Glu738=	synonymous_variant	18/18	1	NM_019098.5	P1
CNGB3	ENST00000517327.5	c.276+2669A>G		intron_variant		3
CNGB3	ENST00000681546.1	n.2034A>G		non_coding_transcript_exon_variant	13/13
CNGB3	ENST00000681746.1	c.*625A>G		3_prime_UTR_variant, NMD_transcript_variant	19/19

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12503 AN: 152062 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.0701

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0616

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0870 AC: 21748 AN: 250102 Hom.: 981 AF XY: 0.0871 AC XY: 11780 AN XY: 135178

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.0781

Gnomad ASJ exome AF: 0.0601

Gnomad EAS exome AF: 0.0881

Gnomad SAS exome AF: 0.0819

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0912

Gnomad OTH exome AF: 0.0862

GnomAD4 exome AF: 0.0892 AC: 130163 AN: 1458706 Hom.: 6080 Cov.: 30 AF XY: 0.0887 AC XY: 64337 AN XY: 725714

Gnomad4 AFR exome AF: 0.0688

Gnomad4 AMR exome AF: 0.0779

Gnomad4 ASJ exome AF: 0.0594

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.0900

Gnomad4 OTH exome AF: 0.0900

GnomAD4 genome AF: 0.0822 AC: 12516 AN: 152180 Hom.: 575 Cov.: 32 AF XY: 0.0830 AC XY: 6172 AN XY: 74400

Gnomad4 AFR AF: 0.0701

Gnomad4 AMR AF: 0.0616

Gnomad4 ASJ AF: 0.0623

Gnomad4 EAS AF: 0.0998

Gnomad4 SAS AF: 0.0753

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.0728

Alfa AF: 0.0875 Hom.: 305

Bravo AF: 0.0790

Asia WGS AF: 0.117 AC: 408 AN: 3478

EpiCase AF: 0.0829

EpiControl AF: 0.0806

ClinVar

Significance: Benign

Submissions summary: Benign:8

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Achromatopsia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.82
CADD	Benign	2.4
DANN	Benign	0.63

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: rs3735970; hg19: chr8-87588248; COSMIC: COSV100181309;