8-86739620-GTTTTTT-GTTTT

Variant names:

• chr8-86739620-GTT-G
• rs78198409
• NM_019098.5:c.211+33_211+34delAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_019098.5(CNGB3):​c.211+33_211+34delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,471,490 control chromosomes in the GnomAD database, including 206 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (194 hom., cov: 0)
  • Exomes 𝑓: 0.040 (12 hom.)
• Consequence: CNGB3 NM_019098.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.129
• Publications: 2 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)

CNGB3-AS1 (HGNC:58258):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-86739620-GTT-G is Benign according to our data. Variant chr8-86739620-GTT-G is described in ClinVar as Benign. ClinVar VariationId is 1267752.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 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.211+33_211+34delAA		intron	N/A	NP_061971.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.211+33_211+34delAA		intron	N/A	ENSP00000316605.5	Q9NQW8-1
	CNGB3-AS1	ENST00000519041.1	TSL:3	n.449-21215_449-21214delTT		intron	N/A
	CNGB3	ENST00000519777.1	TSL:2	n.193+33_193+34delAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0555 AC: 7144 AN: 128806 Hom.: 195 Cov.: 0

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0733

Gnomad ASJ AF: 0.0697

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0721

GnomAD4 exome AF: 0.0405 AC: 54318 AN: 1342674 Hom.: 12 AF XY: 0.0409 AC XY: 27330 AN XY: 667488

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0694 AC: 2052 AN: 29584

American (AMR) AF: 0.0819 AC: 3032 AN: 37024

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 1315 AN: 23798

East Asian (EAS) AF: 0.110 AC: 4023 AN: 36704

South Asian (SAS) AF: 0.0427 AC: 3227 AN: 75624

European-Finnish (FIN) AF: 0.0626 AC: 2618 AN: 41838

Middle Eastern (MID) AF: 0.0850 AC: 439 AN: 5166

European-Non Finnish (NFE) AF: 0.0337 AC: 34969 AN: 1037468

Other (OTH) AF: 0.0476 AC: 2643 AN: 55468

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0555 AC: 7150 AN: 128816 Hom.: 194 Cov.: 0 AF XY: 0.0581 AC XY: 3589 AN XY: 61800

African (AFR) AF: 0.0705 AC: 2457 AN: 34846

American (AMR) AF: 0.0736 AC: 954 AN: 12960

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 219 AN: 3140

East Asian (EAS) AF: 0.138 AC: 611 AN: 4442

South Asian (SAS) AF: 0.0476 AC: 190 AN: 3990

European-Finnish (FIN) AF: 0.0622 AC: 400 AN: 6434

Middle Eastern (MID) AF: 0.124 AC: 30 AN: 242

European-Non Finnish (NFE) AF: 0.0360 AC: 2165 AN: 60176

Other (OTH) AF: 0.0705 AC: 124 AN: 1760

Alfa AF: 0.0281 Hom.: 244

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
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: rs78198409; hg19: chr8-87751848; COSMIC: COSV60691899;