rs3735970

Variant names:

• chr8-86576020-T-C
• rs3735970
• NM_019098.5:c.2214A>G
• CNGB3 p.Glu738Glu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019098.5(CNGB3):​c.2214A>G​(p.Glu738Glu) 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
• Publications: 15 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 -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 VariationId is 166903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2214A>G	p.Glu738Glu	synonymous	Exon 18 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.2214A>G	p.Glu738Glu	synonymous	Exon 18 of 18	ENSP00000316605.5	Q9NQW8-1
	CNGB3	ENST00000517327.5	TSL:3	c.276+2669A>G		intron	N/A	ENSP00000428329.1	H0YAZ4
	CNGB3	ENST00000681546.1		n.2034A>G		non_coding_transcript_exon	Exon 13 of 13

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

GnomAD2 exomes AF: 0.0870 AC: 21748 AN: 250102 AF XY: 0.0871

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 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

African (AFR) AF: 0.0688 AC: 2296 AN: 33392

American (AMR) AF: 0.0779 AC: 3477 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 1553 AN: 26124

East Asian (EAS) AF: 0.113 AC: 4501 AN: 39678

South Asian (SAS) AF: 0.0796 AC: 6816 AN: 85674

European-Finnish (FIN) AF: 0.109 AC: 5830 AN: 53378

Middle Eastern (MID) AF: 0.0593 AC: 340 AN: 5738

European-Non Finnish (NFE) AF: 0.0900 AC: 99924 AN: 1109830

Other (OTH) AF: 0.0900 AC: 5426 AN: 60266

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

African (AFR) AF: 0.0701 AC: 2910 AN: 41520

American (AMR) AF: 0.0616 AC: 941 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 216 AN: 3468

East Asian (EAS) AF: 0.0998 AC: 516 AN: 5172

South Asian (SAS) AF: 0.0753 AC: 363 AN: 4818

European-Finnish (FIN) AF: 0.112 AC: 1192 AN: 10604

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6131 AN: 68000

Other (OTH) AF: 0.0728 AC: 154 AN: 2114

Alfa AF: 0.0874 Hom.: 307

Bravo AF: 0.0790

Asia WGS AF: 0.117 AC: 408 AN: 3478

EpiCase AF: 0.0829

EpiControl AF: 0.0806

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3735970;

hg19: chr8-87588248;

COSMIC: COSV100181309;