8-86668054-C-T

Variant names:

• chr8-86668054-C-T
• rs16916632
• NM_019098.5:c.608G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019098.5(CNGB3):​c.608G>A​(p.Arg203Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00948 in 1,613,782 control chromosomes in the GnomAD database, including 1,054 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R203L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (552 hom., cov: 31)
  • Exomes 𝑓: 0.0056 (502 hom.)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.856
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015887618).
• BP6: Variant 8-86668054-C-T is Benign according to our data. Variant chr8-86668054-C-T is described in ClinVar as Benign. ClinVar VariationId is 261089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019098.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	NM_019098.5	MANE Select	c.608G>A	p.Arg203Gln	missense	Exon 5 of 18	NP_061971.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.608G>A	p.Arg203Gln	missense	Exon 5 of 18	ENSP00000316605.5
	CNGB3	ENST00000681746.1		n.608G>A		non_coding_transcript_exon	Exon 5 of 19	ENSP00000505959.1
	CNGB3	ENST00000680314.1		n.*110G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7121 AN: 151846 Hom.: 549 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00522

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0147 AC: 3695 AN: 251418 AF XY: 0.0115

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.00943

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00696

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00558 AC: 8159 AN: 1461820 Hom.: 502 Cov.: 32 AF XY: 0.00513 AC XY: 3730 AN XY: 727222

African (AFR) AF: 0.163 AC: 5469 AN: 33454

American (AMR) AF: 0.0106 AC: 475 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00383 AC: 152 AN: 39696

South Asian (SAS) AF: 0.0112 AC: 963 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000311 AC: 346 AN: 1111982

Other (OTH) AF: 0.0120 AC: 723 AN: 60390

GnomAD4 genome AF: 0.0470 AC: 7137 AN: 151962 Hom.: 552 Cov.: 31 AF XY: 0.0443 AC XY: 3289 AN XY: 74240

African (AFR) AF: 0.161 AC: 6682 AN: 41390

American (AMR) AF: 0.0176 AC: 269 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00523 AC: 27 AN: 5158

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 67988

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0182 Hom.: 416

Bravo AF: 0.0543

ESP6500AA AF: 0.154 AC: 679

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0174 AC: 2113

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Achromatopsia (1)
-	-	1	Achromatopsia 3 (1)
-	-	1	not specified (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.98
DANN	Benign	0.83
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.86
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.25
Sift	Benign	0.25	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.040
MPC		0.029
ClinPred		0.0031	T
GERP RS		-6.8
Varity_R		0.037
gMVP		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16916632; hg19: chr8-87680282;