NM_019098.5:c.339-10dupT

Variant names:

• chr8-86671107-G-GA
• rs200792506
• NM_019098.5:c.339-10dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_019098.5(CNGB3):​c.339-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,972 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0096 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: CNGB3 NM_019098.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.108
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 8-86671107-G-GA is Benign according to our data. Variant chr8-86671107-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261087.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00958 (1451/151460) while in subpopulation AFR AF = 0.033 (1364/41310). AF 95% confidence interval is 0.0316. There are 22 homozygotes in GnomAd4. There are 701 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD,Unknown gene

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.339-10dupT		intron	N/A	NP_061971.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.339-10dupT		intron	N/A	ENSP00000316605.5
	CNGB3	ENST00000680314.1		n.100-10dupT		intron	N/A
	CNGB3	ENST00000681746.1		n.339-10dupT		intron	N/A	ENSP00000505959.1

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1452 AN: 151344 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00626

GnomAD2 exomes AF: 0.00246 AC: 615 AN: 249788 AF XY: 0.00187

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00102 AC: 1488 AN: 1460512 Hom.: 17 Cov.: 32 AF XY: 0.000888 AC XY: 645 AN XY: 726576

African (AFR) AF: 0.0355 AC: 1188 AN: 33448

American (AMR) AF: 0.00143 AC: 64 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52674

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5680

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1111620

Other (OTH) AF: 0.00177 AC: 107 AN: 60348

GnomAD4 genome AF: 0.00958 AC: 1451 AN: 151460 Hom.: 22 Cov.: 32 AF XY: 0.00947 AC XY: 701 AN XY: 73998

African (AFR) AF: 0.0330 AC: 1364 AN: 41310

American (AMR) AF: 0.00407 AC: 62 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67816

Other (OTH) AF: 0.00619 AC: 13 AN: 2100

Alfa AF: 0.000525 Hom.: 0

Bravo AF: 0.0107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Achromatopsia (2)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200792506; hg19: chr8-87683335;