NM_019098.5:c.919A>G

Variant names:

• chr8-86647872-T-C
• rs13265557
• NM_019098.5:c.919A>G

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.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. 16/21 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
• Publications: 23 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=0.0023343265).
• BP6: Variant 8-86647872-T-C is Benign according to our data. Variant chr8-86647872-T-C is described in ClinVar as Benign. ClinVar VariationId is 261092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	NM_019098.5	MANE Select	c.919A>G	p.Ile307Val	missense	Exon 8 of 18	NP_061971.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.919A>G	p.Ile307Val	missense	Exon 8 of 18	ENSP00000316605.5	Q9NQW8-1
	CNGB3	ENST00000681546.1		n.739A>G		non_coding_transcript_exon	Exon 3 of 13
	CNGB3	ENST00000681746.1		n.919A>G		non_coding_transcript_exon	Exon 8 of 19	ENSP00000505959.1	A0A5J6DSN8

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

GnomAD2 exomes AF: 0.0692 AC: 17292 AN: 249968 AF XY: 0.0710

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 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

African (AFR) AF: 0.0460 AC: 1517 AN: 32986

American (AMR) AF: 0.0675 AC: 3009 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 894 AN: 25908

East Asian (EAS) AF: 0.0793 AC: 3129 AN: 39438

South Asian (SAS) AF: 0.107 AC: 9141 AN: 85640

European-Finnish (FIN) AF: 0.0834 AC: 4453 AN: 53372

Middle Eastern (MID) AF: 0.0411 AC: 234 AN: 5696

European-Non Finnish (NFE) AF: 0.0620 AC: 67732 AN: 1092562

Other (OTH) AF: 0.0669 AC: 3983 AN: 59530

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

African (AFR) AF: 0.0479 AC: 1985 AN: 41454

American (AMR) AF: 0.0546 AC: 828 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 116 AN: 3446

East Asian (EAS) AF: 0.0651 AC: 337 AN: 5178

South Asian (SAS) AF: 0.110 AC: 529 AN: 4826

European-Finnish (FIN) AF: 0.0900 AC: 956 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4177 AN: 67290

Other (OTH) AF: 0.0610 AC: 128 AN: 2098

Alfa AF: 0.0608 Hom.: 615

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Achromatopsia 3 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Achromatopsia (1)
-	-	1	Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.33
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13265557; hg19: chr8-87660100; COSMIC: COSV60696755;