rs13265557

Positions:

• chr8-86647872-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019098.5(CNGB3):​c.919A>G​(p.Ile307Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,590,968 control chromosomes in the GnomAD database, including 3,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (310 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3450 hom.)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.332

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023343265).
• BP6: Variant 8-86647872-T-C is Benign according to our data. Variant chr8-86647872-T-C is described in ClinVar as [Benign]. Clinvar id is 261092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86647872-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.919A>G	p.Ile307Val	missense_variant	8/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.505A>G	p.Ile169Val	missense_variant	6/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.919A>G	p.Ile307Val	missense_variant	8/18	1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000681546.1	n.739A>G		non_coding_transcript_exon_variant	3/13
CNGB3	ENST00000681746.1	c.919A>G	p.Ile307Val	missense_variant, NMD_transcript_variant	8/19			ENSP00000505959

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9085 AN: 151164 Hom.: 308 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.0645

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0900

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0592

GnomAD3 exomes AF: 0.0692 AC: 17292 AN: 249968 Hom.: 701 AF XY: 0.0710 AC XY: 9599 AN XY: 135124

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.0682

Gnomad ASJ exome AF: 0.0357

Gnomad EAS exome AF: 0.0534

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0862

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0654 AC: 94092 AN: 1439684 Hom.: 3450 Cov.: 27 AF XY: 0.0666 AC XY: 47794 AN XY: 717442

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.0675

Gnomad4 ASJ exome AF: 0.0345

Gnomad4 EAS exome AF: 0.0793

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0669

GnomAD4 genome AF: 0.0602 AC: 9103 AN: 151284 Hom.: 310 Cov.: 32 AF XY: 0.0619 AC XY: 4579 AN XY: 73992

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.0546

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.0651

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.0900

Gnomad4 NFE AF: 0.0621

Gnomad4 OTH AF: 0.0610

Alfa AF: 0.0609 Hom.: 380

Bravo AF: 0.0552

TwinsUK AF: 0.0588 AC: 218

ALSPAC AF: 0.0667 AC: 257

ESP6500AA AF: 0.0520 AC: 229

ESP6500EA AF: 0.0599 AC: 515

ExAC AF: 0.0709 AC: 8606

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Achromatopsia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

not provided Benign:2

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

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 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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.023
DANN	Benign	0.61
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.15	N
MutationTaster	Benign	0.89	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.26
Sift	Benign	0.37	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.020
MPC		0.026
ClinPred		0.00080	T
GERP RS		-6.9
Varity_R		0.036
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13265557; hg19: chr8-87660100; COSMIC: COSV60696755;