chr8-86611673-T-C

Variant names:

• chr8-86611673-T-C
• rs772725807
• NM_019098.5:c.1579-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_019098.5(CNGB3):​c.1579-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNGB3 NM_019098.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.61
• 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: 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0345679 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 15, new splice context is: tatggggttgtgatacacAGatg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86611673-T-C is Pathogenic according to our data. Variant chr8-86611673-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 427705.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1579-2A>G		splice_acceptor 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.1579-2A>G		splice_acceptor intron	N/A	ENSP00000316605.5	Q9NQW8-1
	CNGB3	ENST00000681546.1		n.1399-2A>G		splice_acceptor intron	N/A
	CNGB3	ENST00000681746.1		n.1579-2A>G		splice_acceptor intron	N/A	ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249908 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450092 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 722144

African (AFR) AF: 0.00 AC: 0 AN: 33212

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101800

Other (OTH) AF: 0.00 AC: 0 AN: 59960

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000812 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Achromatopsia (1)
1	-	-	Achromatopsia 3 (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.6
GERP RS		4.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs772725807; hg19: chr8-87623901;